Oxazolone derivatives and their use as anti-Helicobacter pylori agent

ABSTRACT

An anti- Helicobacter pylori  agent comprising a compound represented by the formula:                    
     wherein A represents an aromatic ring group which may be substituted; R 1  and R 2 , whether identical or not, each represent a hydrogen atom or a hydrocarbon group which may be substituted; R 3  and R 4 , whether identical or not, each represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified; or a salt thereof.

This application is a 371 of PCT/JP97/02157 filed Jun. 24, 1997.

TECHNICAL FIELD

The present invention relates to an anti-Helicobacter pylori agentcomprising an oxazolin-4-one derivative useful as a therapeutic agentfor gastric and duodenal ulcer etc.

BACKGROUND ART

As therapeutic agents for ulcer, there have been developed antacids,anticholinergic agents, antigastrin agents, gastrointestinal hormones,antipepsine agents, histamine H₂ receptor antagonists, tissue repairingagents, mucosa-protecting agents, microcirculation-improving agents,proton pump inhibitors etc. The development of histamine H₂ receptorantagonists and proton pump inhibitors, both possessing potent acidsecretion-suppressing activity, in particular, has facilitated ulcertreatment.

However, these therapeutic agents for ulcer are unsatisfactory in termsof suppressing effect on recurrent ulcer. On the other hand,Helicobacter pylori, a gram-negative microaerophilic bacterium belongingto the genus Helicobacter, has been suggested as a potential major causeof recurrence of gastritis, duodenal ulcer, gastric ulcer etc. Althoughmany antibacterial agents readily inhibit the proliferation of therespective microorganisms belonging to the genus Helicobacter in vitro,their efficacy in humans and animal experiments is very low whenadministered singly in vivo.

Various diseases caused by Helicobacter pylori as such are treated bychemotherapies such as double chemotherapy with a bismuth preparationand an antibiotic, and triple chemotherapy with a bismuth preparation,metronidazole (U.S. Pat. No. 2,944,061) and either tetracycline (e.g.,U.S. Pat. No. 2,712,517) or amoxicillin (U.S. Pat. No. 3,192,198).Metronidazole, an imidazole derivative possessing anti-Helicobacterpylori activity, is used in combination with antibiotics. These bismuthpreparations, antibiotics, metronidazole etc. are administered orally.Also, clinical studies have shown that eradication of this microorganismresults in healing and decreased recurrence rates in ulcer.

However, these bismuth preparations, antibiotics, metronidazole etc.must be administered at high daily doses to maintain sufficientconcentrations to inhibit Helicobacter pylori proliferation at the sitesof their proliferation, resulting in many problems, including adverseeffects such as vomiting and diarrhea.

There have been developed various compounds possessing anti-Helicobacterpylori activity. For example, Japanese Patent Unexamined Publication No.117268/1993 discloses a pyridine derivative possessing anti-Helicobacterpylori activity, and European Patent EPO 535528A1 discloses an imidazolederivative possessing anti-Helicobacter pylori activity.

DISCLOSURE OF INVENTION

After extensive investigation in view of the above problems, the presentinventors found that a particular oxazolin-4-one derivative exhibitsvery specific and excellent antibacterial activity against the bacteriaof the genus Helicobacter, represented by Helicobacter pylori. Theinventors conducted further investigation based on this finding, anddeveloped the present invention.

Accordingly, the present invention relates to

(1) an anti-Helicobacter pylori composition comprising a compound of theformula:

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R³ and R⁴ independently represent a hydrogen atom, ahydrocarbon group which may be substituted, an acyl group, a carbamoylgroup which may be substituted, or a carboxyl group which may beesterified, or a salt thereof, and a pharmacologically acceptablediluent, excipient or carrier,

(2) the anti-Helicobacter pylori composition according to thedescription in (1) above, wherein A is an aromatic heterocyclic groupwhich may be substituted,

(3) the anti-Helicobacter pylori composition according to thedescription in (1) above, wherein A is a group represented by theformula:

wherein ring B is a 6-membered aromatic ring which may be substituted, Xrepresents CH or N, Y represents O, S or —N—R⁵ (R⁵ represents a hydrogenatom or a hydrocarbon group which may be substituted),

(4) the anti-Helicobacter pylori composition according to thedescription in (1) above, wherein A is a group represented by theformula:

wherein ring B is a 6-membered aromatic ring which may be substituted,R⁵ represents a hydrogen atom or a hydrocarbon group which may besubstituted,

(5) the anti-Helicobacter pylori composition according to thedescription in (1) above, wherein A represented indolyl which may besubstituted by 1 to 3 substituents selected from the group consisting ofhydroxyl, halogen, nitro, cyano, lower alkyl which may be substituted by1 to 5 halogens and lower alkoxy which may be substituted by 1 to 5halogens, R¹ and R² independently represent hydrogen or lower alkylwhich may be substituted by 1 to 5 halogens, R³ and R⁴ independentlyrepresent hydrogen or lower alkyl,

(6) the anti-Helicobacter pylori composition according to thedescription in (5) above, wherein A is indolyl, R¹ and R³ are hydrogen,and R² and R⁴ are C₁₋₇ alkyl,

(7) the anti-Helicobacter pylori composition according to thedescription in (6) above, wherein A is 3-indolyl, R² and R⁴ are methyl,

(8) the anti-Helicobacter pylori composition according to thedescription in (1) above, wherein the compound is indolmycin,

(9) the anti-Helicobacter pylori composition according to thedescription in (1) above, as an agent for prevention or treatment of adisease associated with Helicobacter pylori infection,

(10) the anti-Helicobacter pylori composition according to thedescription in (9) above, wherein the disease associated withHelicobacter pylori infection is gastric or duodenal ulcer, gastritis orgastric cancer,

(11) the anti-Helicobacter pylori composition according to thedescription in (1) above, which is used in combination with anantibacterial agent,

(12) the anti-Helicobacter pylori composition according to thedescription in (1) above, which is used in combination with antiulceragent,

(13) the anti-Helicobacter pylori composition according to thedescription in (1) above, which is used in combination withantibacterial agent and antiulcer agent,

(14) use of compound of the formula:

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R³ and R⁴ independently represent a hydrogen atom, ahydrocarbon group which may be substituted, an acyl group, a carbamoylgroup which may be substituted, or a carboxyl group which may beesterified, or a salt thereof for the preparation of ananti-Helicobacter pylori agent,

(15) a method for prevention or treatment of a disease associated withHelicobacter pylori infection in a mammal which comprises administeringto a subject in need an effective amount of a compound of the formula(I):

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R³ and R⁴ independently represent a hydrogen atom, ahydrocarbon group which may be substituted, an acyl group, a carbamoylgroup which may be substituted, or a carboxyl group which may beesterified, or a salt thereof,

(16) a method for producing an anti-Helicobacter pylori compositioncomprising mixing a compound of the formula (I):

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R³ and R⁴ independently represent a hydrogen atom, ahydrocarbon group which may be substituted, an acyl group, a carbamoylgroup which may be substituted, or a carboxyl group which may beesterified, or a salt thereof with a pharmacologically acceptablediluent, excipient or/and carrier,

(17) a compound of the formula:

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R^(3′) and R^(4′) independently represent a hydrogenatom or a hydrocarbon group which may be substituted, or a salt thereof,provided that (1) when A is 3-indolyl, R¹ and R^(3′) are hydrogen and R²is methyl, R^(4′) is neither C₃₋₆ cycloalkyl nor mono-substituted C₁₋₄alkyl wherein said substituent is selected from halogen, hydroxyl, loweralkoxy, lower thioalkyl, aryl, or an unsaturated 2-4 carbon atomsside-chain and (2) when A is 3-indolyl, R¹ and R^(3′) are hydrogen andR² is C₁₋₃ alkyl, R^(4′) is not selected from hydrogen, phenyl, anisyl,toluidyl and C₁₋₄ alkyl,

(18) a compound of the formula:

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R^(3′) is a hydrogen atom or a hydrocarbon groupwhich may be substituted, R^(4″) is an acyl group or a carbamoyl groupwhich may be substituted, or a salt thereof, provided that when A is3-indolyl, R¹ is hydrogen and R² and R^(3′) are methyl, R^(4″) isneither a C₂₋₅ alkanoyl or an mono-substituted C₂₋₅ alkanoyl whereinsaid substituent is selected from amino, halogen, phenyl,p-hydroxyphenyl, or lower alkoxy, nor a carbamoyl group substituted byC₁₋₄ alkyl, C₃₋₆ cycloalkyl or phenyl,

(19) a compound of the formula:

wherein A represents an aromatic group which may be substituted, R¹ andR² independently represent a hydrogen atom or a hydrocarbon group whichmay be substituted, R^(3′) is a hydrogen atom or a hydrocarbon groupwhich may be substituted, R⁴″′ is a carboxyl group which may beesterified, or a salt thereof,

(20) the compound according to the description in (19) above, wherein Ais indolyl, R¹ and R² independently represent a hydrogen atom or methyl,R^(3′) is methyl and R⁴″′ is a carboxyl group which is-esterified,

(21) a method of producing indolmycin by culturing the Streptomyces sp.HC-21 strain in a medium to produce and accumulate indolmycin in theculture broth, and harvesting the indolmycin, and

(22) the Streptomyces sp. HC-21 strain which assimilates L-rhamnose andwhose spores have a spiny surface.

The “aromatic ring group which may be substituted” represented by A informula (I) is exemplified by monocyclic or condensed polycyclicaromatic hydrocarbon groups or aromatic heterocyclic groups. Sucharomatic hydrocarbon groups include, for example, phenyl, naphthyl,anthryl, phenanthryl and acenaphthylenyl, with preference given tophenyl, 1-naphthyl, 2-naphthyl etc.

The aromatic heterocyclic groups include, for example, aromaticmonocyclic heterocyclic groups such as furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and1,2,4-triazolo[4,3-b]pyridazinyl. Among aromatic condensed heterocyclicgroup, indolyl is preferable and 3-indolyl is more preferable.

Substituents for the “aromatic ring group or aromatic heterocyclic groupwhich may be substituted” represented by A in formula (I) include, forexample, hydroxyl group, halogens (e.g., fluorine, chlorine, bromine,iodine), nitro, cyano, lower alkyls that may be substituted by 1 to 5halogens (e.g., fluorine, chlorine, bromine, iodine), lower alkoxys thatmay be substituted by 1 to 5 halogens (e.g., fluorine, chlorine,bromine, iodine) benzyloxy and C₁₋₄ alkoxy carbonyl (e.g. methoxycarbonyl, ethoxy carbony, propoxy carbonyl, butoxy carbonyl). Such loweralkyls include, for example, alkyl groups having 1 to 4 carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyland tert-butyl, with preference given to methyl and ethyl. Such loweralkoxys include alkoxy groups having 1 to 4 carbon atoms, such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxyand tert-butoxy, with preference given to methoxy and ethoxy. It ispreferable that 1 to 3 (preferably 1 to 2) of these substituents,whether identical or not, be present. Substituents for the “aromaticring group or aromatic heterocyclic group which may be substituted”represented by A also include alkylene dioxo such as methylene dioxo andethylene dioxo.

The “hydrocarbon group which may be substituted” represented by R¹ or R²in formula (I) include aliphatic chain hydrocarbon groups, alicyclichydrocarbon groups and aryl groups, with preference given to aliphaticchain hydrocarbon groups.

Such aliphatic chain hydrocarbon groups include linear or branchedaliphatic hydrocarbon groups such as alkyl groups, alkenyl groups andalkynyl groups. Particularly preferred are lower alkyl groups, loweralkenyl groups, lower alkynyl groups etc. Such lower alkyls include, forexample, C₁₋₇ alkyls such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyland n-heptyl. Preferred are C₁₋₃ alkyls such as methyl, ethyl andpropyl, with greater preference given to C₁₋₂ alkyls such as methyl andethyl. Such lower alkenyl groups include, for example, C₂₋₆ alkenylgroups such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, withpreference given to C₂₋₅ alkenyls such as vinyl, allyl, isopropenyl,2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and3-methyl-2-butenyl. Such lower alkynyl groups include, for example, C₂₋₆alkynyls such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, with preference given toC₂₋₄ alkynyls such as ethynyl, 1-propynyl and 2-propynyl.

Such alicyclic hydrocarbon groups include saturated or unsaturatedalicyclic hydrocarbon groups such as cycloalkyl groups, cycloalkenylgroups and cycloalkadienyl groups. Such cycloalkyl groups are preferablycycloalkyl groups having 3 to 9 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andcyclononyl, with greater preference given to C₃₋₆ cycloalkyl groups suchas cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Suchcycloalkenyl groups include, for example, C₃₋₆ cycloalkenyls such as2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl. Suchcycloalkadienyl groups include, for example, C₄₋₆ cycloalkadienyls suchas 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and2,5-cyclohexadien-1-yl.

The aryl groups in the hydrocarbon groups include monocyclic orcondensed polycyclic aromatic hydrocarbon groups such as phenyl,naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preferencegiven to phenyl, 1-naphthyl, 2-naphthyl etc.

Substituents for the “hydrocarbon group which may be substituted”represented by R¹ or R² in formula (I) include aryl groups which may besubstituted, cycloalkyl or cycloalkenyl groups which may be substituted,heterocyclic groups that may be substituted, amino group that may besubstituted, hydroxyl group which may be substituted, thiol group whichmay be substituted, and halogens (e.g., fluorine, chlorine, bromine,iodine). One to five (preferably 1 to 3) of these optionally chosensubstituents may be present. Such aryl groups which may be substitutedinclude phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, withpreference given to phenyl, 1-naphthyl and 2-naphthyl. Substituents forsuch aryl groups which may be substituted include alkoxy groups having 1to 3 carbon atoms (e.g., methoxy, ethoxy, propoxy), halogen atoms (e.g.,fluorine, chlorine, bromine, iodine) and alkyl groups having 1 to 3carbon atoms (e.g., methyl, ethyl, propyl); 1 to 2 of these optionallychosen substituents may be present. Such cycloalkyl groups which may besubstituted include C₃₋₇ cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The kinds andnumber of substituents for such cycloalkyl groups which may besubstituted are the same as those for the substituents theabove-described aryl group that may be substituted. Such cycloalkenylgroups which may be substituted include C₃₋₆ cycloalkenyl groups such ascyclopropanyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. The kindsand number of substituents for such cycloalkenyl groups which may besubstituted are the same as those for the substituents for theabove-described aryl group that may be substituted. Such heterocyclicgroups which may be substituted for include aromatic heterocyclic groupshaving at least 1 hetero atom selected from oxygen, sulfur or nitrogenas a ring-constituting atom (ring atom), and saturated or unsaturatednon-aromatic heterocyclic groups (aliphatic heterocyclic groups), withpreference given to aromatic heterocyclic groups. Such aromaticheterocyclic groups include aromatic monocyclic heterocyclic groups(e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl) and aromatic condensed heterocyclic groups (e.g.,benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl,benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl), withpreference given to furyl, thienyl, indolyl, isoindolyl, pyrazinyl,pyridyl, pyrimidinyl etc. Such non-aromatic heterocyclic groups include,for example, oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl and piperazinyl. Substituents for such heterocyclicgroups which may be substituted for include alkyl groups having 1 to 3carbon atoms (e.g., methyl, ethyl, propyl). Substituents for such aminogroup which may be substituted for, hydroxyl group that may besubstituted for, and thiol group that may be substituted for, include,for example, lower (C₁₋₃) alkyl groups (e.g., methyl, ethyl, propyl).When the “hydrocarbon group which may be a substituted” represented byR¹ or R² is an alicyclic hydrocarbon group or an aryl group, thesubstituent may also be an alkyl group having 1 to 3 carbon atoms (e.g.,methyl, ethyl, propyl).

With respect to the formula (I), the preferable combination of R¹ and R²is that R¹ is hydrogen and R² is C₁₋₃ alkyl which may be substituted by1 to 5 halogens.

The hydrocarbon group and the substituent in the “hydrocarbon groupwhich may be substituted” represented by R³ or R⁴ in formula (I) andrepresented by R^(3′) or R^(4′) in formula (I′) are exemplified by thesame hydrocarbon groups and substituents mentioned to exemplify thehydrocarbon group and substituent for R¹ and R² above, respectively.

With respect to the formula (I), the preferable combination of R³ and R⁴is that R³ is hydrogen and R⁴ is C₁₋₃ alkyl.

The acyl group represented by R³ or R⁴ in formula (I) is exemplified byaliphatic acyl groups such as alkanoyl groups, alkenoyl groups,cycloalkanecarbonyl groups and alkanesulfonyl groups; aromatic acylgroups such as aroyl groups, arylalkanoyl groups, arylalkenoyl groupsand arenesulfonyl groups; heterocyclic aromatic acyl groups such asaromatic heterocyclic carbonyl groups and aromatic heterocyclic alkanoylgroups; and non-aromatic heterocyclic carbonyl groups (aliphaticheterocyclic carbonyl groups).

“Alkanoyl groups” mean alkylcarbonyl groups, preferable examples thereofincluding lower alkanoyl groups having 1 to 8 carbon atoms, such asformyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl and hexanoyl.

“Alkenoyl groups” mean alkenylcarbonyl groups, preferable examplesthereof including C₃₋₆ alkenoyl groups such as acryloyl, methacryloyl,crotonoyl and isocrotonoyl.

“Cycloalkanecarbonyl groups” mean cycloalkylcarbonyl groups, preferableexamples thereof including those having 4 to 7 carbon atoms, such ascyclopropanecarbonyl groups, cyclobutanecarbonyl groups,cyclopentanecarbonyl groups and cyclohexanecarbonyl groups.

“Alkanesulfonyl groups” mean alkylsulfonyl groups, preferable examplesthereof including those having 1 to 4 carbon atoms, such as mesyl,ethanesulfonyl and propanesulfonyl.

“Aroyl groups” mean arylcarbonyl groups, preferable examples thereofincluding those having 7 to 11 carbon atoms, such as benzoyl, p-toluoyl,1-naphthoyl and 2-naphthoyl.

“Arylalkanoyl groups” mean alkylcarbonyl groups substituted for by anaryl group, preferable examples thereof including C₆₋₈ aryl-C₂₋₅alkanoyl groups such as phenylacetyl, phenylpropionyl, hydroatropoyl andphenylbutyryl.

“Arylalkenoyl groups” mean alkenylcarbonyl groups substituted for by anaryl group, preferable examples thereof including C₆₋₈ aryl-C₃₋₅alkenoyl groups such as cinnamoyl and atropoyl.

“Arenesulfonyl groups” mean arylsulfbnyl groups, preferable examplesthereof including those having 6 to 8 carbon atoms, such asbenzenesulfonyl and p-toluenesulfonyl.

Preferable examples of “aromatic heterocyclic carbonyl groups” includefuroyl, thenoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl,oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl andpyrazolecarbonyl.

“Aromatic heterocyclic alkanoyl groups” mean alkylcarbonyl groupssubstituted by an aromatic heterocyclic group, preferable examplesthereof including aromatic heterocyclic ring-C₂₋₅ alkanoyl groups suchas thienylacetyl, thienylpropanoyl, furylacetyl, thiazolylacetyl,1,2,4-thiadiazolylacetyl and pyridylacetyl.

Preferable examples of “non-aromatic heterocyclic carbonyl groups”include aliphatic heterocyclic carbonyls such as azetidinylcarbonyl,pyrrolidinylcarbonyl and piperidinylcarbonyl.

The carbamoyl group which may be substituted represented by R³ or R⁴ informula (I) and represented by R^(4′) in formula (I″), is exemplified by“N-monosubstitutional carbamoyl groups” and “N,N-disubstitutionalcarbamoyl groups,” as well as non-substitutional carbamoyl. An“N-monosubstitutional carbamoyl group” means a carbamoyl group havingone substituent on nitrogen. Examples of said substituent include C₁₋₆alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,hexyl), C₃₋₆ cycloalkyl groups (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl), aryl groups (e.g., phenyl, 1-naphthyl,2-naphthyl), aralkyl groups (e.g., benzyl, phenethyl) and heterocyclicgroups (e.g., the “heterocyclic groups” mentioned to exemplify the“substituent” for the “hydrocarbon residue which may be substituted”represented by R¹ or R² above). Such aryl groups, aralkyl groups andheterocyclic groups may be substituted. Said substituent is exemplifiedby hydroxyl group, amino group which may substituted by 1 or 2 loweralkyls (e.g., those having 1 to 4 carbon atoms, such as methyl, ethyl,propyl, isopropyl and butyl) or acyl groups (e.g., formyl, acetyl,propionyl, benzoyl), halogens (e.g., fluorine, chlorine, bromine,iodine), nitro, cyano, lower alkyls which may be substituted by 1 to 5halogens (e.g., fluorine, chlorine, bromine, iodine) and lower alkoxyswhich may be substituted by 1 to 5 halogens (e.g., fluorine, chlorine,bromine, iodine). Such lower alkyls include, for example, alkyl groupshaving 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl and tert-butyl, with preference given tomethyl and ethyl. Such lower alkoxys include alkoxy groups having 1 to 4carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxyand ethoxy. It is preferable that 1 to 3 (preferably 1 to 2) of thesesubstituents, whether identical or not, be present.

An “N,N-disubstitutional carbamoyl group” means a carbamoyl group havingtwo substituents on a nitrogen atom. Examples of one of saidsubstituents include the same substituents as those mentioned toexemplify the substituent for the “N-monosubstitutional carbamoyl group”above; examples of the other substituent include C₁₋₆ alkyl groups(e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl),C₃₋₆ cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl) and C₆₋₁₀ aralkyl groups (e.g., benzyl, phenethyl). The twosubstituents may form a cyclic amino group in cooperation with thenitrogen atom. In this case, examples of cyclic aminocarbamoyl groupsinclude 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl; and1-piperazinylcarbonyl having a lower alkyl group such as C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl),an aralkyl group such as benzyl and phenethyl, an aryl group such asphenyl, 1-naphthyl and 2-naphthyl, or the like, at the 4-position.

The “carboxyl group which may be esterified” represented by R³ or R⁴ informula (I) and represented by R⁴″′ in formula (I″′), is exemplified by“lower alkoxycarbonyl groups,” “aryloxycarbonyl groups” and“aralkyloxycarbonyl groups,” as well as free carboxyl group.

Preferable examples of “lower alkoxycarbonyl groups” include thosehaving 2 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl and tertpentyloxycarbonyl,with preference given to those having 2 to 4 carbon atoms, such asmethoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

Preferable examples of “aryloxycarbonyl groups” include those having 7to 12 carbon atoms, such as phenoxycarbonyl, 1-naphthoxycarbonyl and2-naphthoxycarbonyl. Preferable examples of “aralkyloxycarbonyl groups”include those having 8 to 10 carbon atoms, such as benzyloxycarbonyl andphenethyloxycarbonyl. These aryloxycarbonyl groups andaralkyloxycarbonyl groups may be substituted; useful substituents areidentical to those mentioned to exemplify the substituent for arylgroups and aralkyl groups in the case of N-monosubstitutional carbamoylgroups.

The “6-membered aromatic ring which may be substituted” represented byring B in formula (II) is exemplified by benzene ring which may besubstituted, and 6-membered aromatic heterocyclic ring that may besubstituted. When ring B represents a benzene ring which may besubstituted, formula (II) represents a group represented by the formula:

wherein ring C may be substituted; X and Y have the same definitions asthose shown above. When ring B represents a 6-membered aromaticheterocyclic ring which may be substituted, the groups represented byformula (II) include, for example, those represented by the followingformulas:

In these formulas, ring D may be substituted; X and Y have the samedefinitions as those shown above.

With respect to the above formulas, the substituents for rings C and Dare identical to those mentioned to exemplify the “substituent” for the“aromatic ring group which may be substituted”, represented by A. Thesesubstituents may bound to any carbon atom of rings C and D.

The “hydrocarbon group which may be substituted” represented by R⁵ informula (II-1) is exemplified by the same hydrocarbon groups as thosementioned to exemplify the hydrocarbon group represented by R¹ or R²,which may be substituted.

With respect to the formula (I), the preferable combination of A, R¹,R², R³ and R⁴ is that A is indolyl, R¹ and R³ are hydrogen, and R² andR⁴ are C₁₋₃ alkyl. The specific examples of the above-describedoxazolin-4-one derivative include indolmycin.

Salts of the compound represented by formula (I), (I′), (I″) or (I″′)include pharmacologically acceptable acid addition salts; acids thatform an acid addition salt include acetic acid, lactic acid, succinicacid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbicacid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid,cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid,hydrogen bromide, hydrogen iodide, sulfamic acid and sulfonic acid.

Examples of the compound represented by the formula (I) are given below.

Compound Number A R¹ R² R³ R⁴  1)

H H H H  2)

H H H CH₃  3)

H H H CH₂CH₃  4)

H H H (CH₂)₂CH₃  5)

H H H CH(CH₃)₂  6)

H H H

 7)

H H H (CH₂)₃CH₃  8)

H CH₃ H H  9)

H CH₃ H CH₃ 10)

H CH₃ H CH₂CH₃ 11)

H CH₃ H (CH₂)₂CH₃ 12)

H CH₃ H CH(CH₃)₂ 13)

H CH₃ H

14)

H CH₃ H (CH₂)₃CH₃ 15)

H CH₃ H CH₂CH(CH₃)₂ 16)

H CH₃ H

17)

H CH₃ H

18)

H CH₃ H

19)

H CH₃ CH₃ CH₃ 20)

H CH₃ CH₂CH₃ CH₂CH₃ 21)

H CH₃ H CH₂CH₂OH 22)

H CH₃ H CH₂CH₂OCH₃ 23)

H CH₃ H CH₂CH₂CN 24)

CH₃ CH₃ H CH₃ 25)

CH₃ CH₃ CH₃ CH₃ 26)

H CH₂CH₃ H CH₃ 27)

H CH₂CH₃ H CH₃ 28)

H (CH₂)₂CH₃ H CH₃ 29)

H (CH₂)₂CH₃ CH₃ CH₃ 30)

H CH(CH₃)₂ H CH₃ 31)

H CH(CH₃)₂ CH₃ CH₃ 32)

H CH₃ CH₃ COCH₃ 33)

H CH₃ CH₃ COCH₂CH₃ 34)

H CH₃ CH₃ CO(CH₂)₂CH₃ 35)

H CH₃ CH₃ COCH(CH₃)₂ 36)

H CH₃ CH₃ CO(CH₂)₃CH₃ 37)

H CH₃ CH₃ CO(CH₂)₄CH₃ 38)

H CH₃ CH₃ CO(CH₂)₅CH₃ 39)

H CH₃ CH₃

40)

H CH₃ CH₃

41)

H CH₃ CH₃

42)

H CH₃ CH₃

43)

H CH₃ CH₃

44)

H CH₃ CH₃

45)

H CH₃ CH₃

46)

H CH₃ CH₃

47)

H CH₃ CH₃

48)

H H H COCH₃ 49)

H H H

50)

H H H CONHCH₃ 51)

H H H CONHCH₂CH₃ 52)

H H H CONH(CH₂)₂CH₃ 53)

H H H CONHCH(CH₃)₂ 54)

H H H CONH(CH₂)₃CH₃ 55)

H H H CONH(CH₂)₅CH₃ 56)

H H H

57)

H H H

58)

H H H

59)

H H H

60)

H CH₃ H CONHCH₃ 61)

H CH₃ H CONHCH₂CH₃ 62)

H CH₃ H CONH(CH₂)₂CH₃ 63)

H CH₃ H CONHCH(CH₃)₂ 64)

H CH₃ H CONH(CH₂)₃CH₃ 65)

H CH₃ H CONH(CH₂)₅CH₃ 66)

H CH₃ H

67)

H CH₃ H

68)

H CH₃ H

69)

H CH₃ H

70)

H CH₃ CH₃ CONHCH₃ 71)

H CH₃ CH₃ CONHCH₂CH₃ 72)

H CH₃ CH₃ CONHCH(CH₃)₂ 73)

H CH₃ CH₃ CONH(CH₂)₂CH₃ 74)

H CH₃ CH₃ CONH(CH₂)₃CH₃ 75)

H CH₃ CH₃ CONH(CH₂)₄CH₃ 76)

H CH₃ CH₃ CONH(CH₂)₅CH₃ 77)

H CH₃ CH₃

78)

H CH₃ CH₃

79)

H CH₃ CH₃

80)

H CH₃ CH₃

81)

H CH₃ CH₃

82)

H CH₃ CH₃

83)

H CH₃ CH₃

84)

H CH₃ CH₃

85)

H CH₃ CH₃

86)

H CH₃ CH₃

87)

H CH₃ CH₃

88)

CH₃ CH₃ CH₃ CONHCH₃ 89)

CH₃ CH₃ CH₃ CONHCH₂CH₃ 90)

CH₃ CH₃ CH₃

91)

CH₃ CH₃ CH₃

92)

H H H

93)

H H H

94)

H H H

95)

H H H

96)

H H H

97)

H H H

98)

H H H

99)

H CH₃ CH₃

100) 

H CH₃ CH₃

101) 

H CH₃ CH₃

102) 

H CH₃ CH₃

103) 

H CH₃ CH₃

104) 

H CH₃ CH₃

105) 

H CH₃ CH₃

106) 

H CH₃ CH₃

107) 

H CH₃ CH₃

108) 

H CH₃ CH₃

109) 

H CH₃ CH₃

110) 

H CH₃ CH₃

111) 

H CH₃ CH₃

112) 

H CH₃ CH₃

113) 

H CH₃ CH₃

114) 

H CH₃ CH₃

115) 

H CH₃ CH₃

116) 

H CH₃ CH₃

117) 

H CH₃ CH₃

118) 

H H H H 119) 

H H H

120) 

H H H

121) 

H CH₃ CH₃ H 122) 

H CH₃ CH₃

123) 

H CH₃ CH₃

124) 

H CH₃ CH₃

125) 

H CH₃ CH₃

126) 

H H H H 127) 

H H H

128) 

H H H

129) 

H CH₃ CH₃ H 130) 

H CH₃ CH₃

131) 

H CH₃ CH₃

132) 

H CH₃ CH₃

133) 

H CH₃ CH₃

134) 

H H H H 135) 

H H H

136) 

H H H

137) 

H CH₃ CH₃ H 138) 

H CH₃ CH₃

139) 

H CH₃ CH₃

140) 

H CH₃ CH₃

141) 

H CH₃ CH₃

142) 

H CH₃ CH₃

143) 

H CH₃ CH₃

144) 

H CH₃ CH₃

145) 

H CH₃ CH₃ COOCH₃ 146) 

H CH₃ CH₃ COOCH₂CH₃ 147) 

H CH₃ CH₃ COO(CH₂)₂CH₃ 148) 

H CH₃ CH₃ COOCH(CH₃)₂ 149) 

H CH₃ CH₃ COO(CH₃)₃CH₃ 150) 

H CH₃ CH₃ COOCH₂CH(CH₃)₃ 151) 

H CH₃ CH₃ COOC(CH₃)₃ 152) 

H CH₃ CH₃ COO(CH₂)₄CH₃ 153) 

H CH₃ CH₃ COO(CH₂)₅CH₃ 154) 

H CH₃ CH₃

155) 

H CH₃ CH₃ SO₂CH₃ 156) 

H CH₃ CH₃ SO₂CH₂CH₃ 157) 

H CH₃ CH₃ SO₂(CH₂)₂CH₃ 158) 

H CH₃ CH₃ SO₂(CH₂)₃CH₃ 159) 

H CH₃ CH₃ SO₂(CH₂)₄CH₃ 160) 

H CH₃ CH₃ SO₂(CH₂)₅CH₃ 161) 

H CH₃ CH₃

162) 

H CH₃ CH₃

163) 

H CH₃ CH₃

164) 

H CH₃ CH₃

165) 

H CH₃ CH₃

166) 

H CH₃ CH₃

The above compounds may be racemates or optical isomers.

Compound (I) or a salt thereof, used for the present invention, iseffective as an antibacterial agent in the prevention or treatment of“duodenal ulcer, gastric ulcer, gastritis (including chronic gastritis),gastric cancer etc.” caused by Helicobacter pylori infection asdescribed above, because it possesses antibacterial activity, especiallypotent antibacterial activity against the bacteria of the genusHelicobacter, represented by Helicobacter pylori.

The preparation of the present invention, containing compound (I) or apharmacologically acceptable salt thereof, can be orally or non-orallyadministered as an antibacterial or antiulcer agent to mammals (e.g.,humans, dogs, cats, monkeys, rats, mice, horses, bovines), oraladministration being normally preferred.

Examples of dosage forms for oral administration include tablets(including sugar-coated tablets and film-coated tablets), pills,granules, powders, capsules (including soft capsules), syrups, emulsionsand suspensions. Examples of dosage forms for non-oral administrationinclude injectable preparations, infusions, drip infusions andsuppositories.

The content of compound (I) or a salt thereof in the preparation of thepresent invention is normally 2 to 85% by weight, preferably 5 to 70% byweight.

For preparing compound (I) or a salt thereof in the above-mentioneddosage forms, known production methods in common use in relevant fieldsare applicable. In producing the above-mentioned dosage forms,excipients, binders, disintegrants, lubricants, sweetening agents,surfactants, suspending agents, emulsifiers etc. in common use in thefield of pharmaceutical making may be added in appropriate amounts asnecessary.

When compound (I) or a salt thereof is prepared as tablets, for example,excipients, binders, disintegrants, lubricants etc. may be contained;when compound (I) or a salt thereof is prepared as pills or granules,excipients, binders, disintegrants etc. may be contained. When compound(I) or a salt thereof is prepared as powders or capsules, excipientsetc. may be contained; when compound (I) or a salt thereof is preparedas syrups, sweetening agents etc. may be contained; when compound (I) ora salt thereof is prepared as emulsions or suspensions, suspendingagents, surfactants, emulsifiers etc. may be contained. Examples ofexcipients include lactose, saccharose, glucose, starch, sucrose,microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodiumhydrogen carbonate, calcium phosphate and calcium sulfate. Examples ofbinders include 5-10% by weight starch glue solutions, 10-20% by weightgum arabic solutions or gelatin solutions, 1-5% by weight tragacanthsolutions, carboxymethyl cellulose solutions, sodium alginate solutionsand glycerol. Examples of disintegrants include starch and calciumcarbonate. Examples of lubricants include magnesium stearate, stearicacid, calcium stearate and purified talc. Examples of sweetening agentsinclude glucose, fructose, invert sugar, sorbitol, xylitol, glycerol andsimple syrups. Examples of surfactants include sodium lauryl sulfate,polysorbate 80, sorbitan monofatty acid ester and stearic acid polyoxyl40. Example of suspending agents include gum arabic, sodium alginate,carboxymethyl cellulose sodium, methyl cellulose and bentonite. Examplesof emulsifiers include gum arabic, tragacanth, gelatin and polysorbate80.

For preparing compound (I) or a salt thereof in the above-mentioneddosage forms, coloring agents, preservatives, flavoring agents,correctives, stabilizers, thickening agents etc. in common use in thefield of pharmaceutical making may be added in appropriate amounts asdesired. The preparation of the present invention, which contains acompound represented bygeneral formula (I) or a pharmaceuticallyacceptable salt thereof, is stable and of low toxicity, and can besafely used. Varying depending on patient condition and body weight,kind of compound, route of administration etc., the daily dose of thepreparation of the present invention is normally 1 to 500 mg, preferablyabout 10 to 200 mg, based on active ingredient content (compound (I) ora salt thereof), per adult (weighing about 60 kg) for oraladministration in patients with gastric ulcer caused by Helicobacterpylori infection.

Within the above-described dose range, no toxicity is seen.

Also, in the preparation of the present invention, compound (I) or asalt thereof can be used in combination with other antibacterial agentsand antiulcer agents.

Other antibacterial agents that can be used in combination with compound(I) or a salt thereof include, for example, nitroimidazole antibiotics(e.g., tinidazole and metronidazole), tetracyclines (e.g., tetracycline,doxycycline and minocycline), penicillins (e.g., amoxicillin, ampicillinand mezlocillin), cephalosporins (e.g., cefaclor, cefadroxil, cefazolin,cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil,ceftazidime and ceftriaxone), carbapenems (e.g., imipenem andmeropenem), aminoglycosides (e.g., paromomycin), macrolide antibiotics(e.g., erythromycin, clarithromycin and azithromycin), lincosamideantibiotics (e.g., clindamycin), rifamycins (e.g., rifampicin) andquinolone antibiotics (e.g., ciprofloxacin, ofloxacin) nitrofurantoin.Antiulcer agents that can be used in combination with compound (I) or asalt thereof include, for example, proto pump inhibitors (e.g.,omeprazole, lansoprazole, pantoprazole, rabeprazole) Histamine H₂antagonists (e.g., ranitidine, cimetidine and famotidine), andmucosa-protecting antiulcer agents (e.g., sofalcone, plaunotol,teprenone, sucralfate).

The above-described other antibacterial agents and antiulcer agents maybe used in combination of two or more kinds. In this case, the dose ofantibacterial agent is normally 1 to 500 mg, preferably 5 to 200 mg, peradult per day in oral administration; the dose of antiulcer agent isnormally 0.5 to 1,000 mg, preferably 1 to 500 mg, per adult per day inoral administration.

The compound of formula (I) or a salt thereof can, for example, beproduced by methods A through E below.

In the above formulas, Z represents a halogen atom or —O—SO₂R⁶ (R⁶represents a lower alkyl group or a substituted phenyl group); the othersymbols have the same definitions as those shown above.

The halogen atom represented by Z in formula (III) is exemplified byfluorine, chlorine, bromine and iodine. The lower alkyl grouprepresented by R⁶ is exemplified by alkyl groups having 1 to 6 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl,1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl and 2-ethylbutyl, with preference given to thosehaving 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl and isobutyl.

Useful substituents for the substituted phenyl group represented by R⁶include, for example, lower alkyl groups (same as those mentioned toexemplify the lower alkyl group represented by R⁶ above), lower alkoxygroups (e.g., those having 1 to 4 carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy and butoxy), halogen atoms (e.g., fluorine,chlorine, bromine, iodine), nitro groups, cyano groups and carboxylgroups.

This method is conducted by reacting compound (III) or a salt thereofwith compound (IV) in the presence of a base. The salt of compound (III)is exemplified by the acid addition salts mentioned to exemplify acidsthat form an acid addition salt with compound (I). This reaction isnormally carried out in a solvent; a solvent that does not interferewith the reaction is chosen as appropriate. Such solvents include, forexample, alcohols such as methanol, ethanol, propanol, isopropanol,butanol and tert-butanol; ethers such as dioxane, tetrahydrofuran,diethyl ether, tert-butyl methyl ether, diisopropyl ether and ethyleneglycol-dimethyl ether; esters such as ethyl formate, ethyl acetate andn-butyl acetate; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane;hydrocarbons such as n-hexane, benzene and toluene; amides such asformamide, N,N-dimethylformamide and N,N-dimethylacetamide; ketones suchas acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrilessuch as acetonitrile and propionitrile; dimethyl sulfoxide, sulfolane,hexamethylphosphoramide and water; these solvents are used as simple ormixed solvents.

Useful bases include, for example, C₁₋₆ alkyl or aryl lithiums such asmethyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium,tert-butyl lithium and phenyl lithium; lithium alkylamides having 2 to 6carbon atoms, such as lithium dimethylamide, lithium diethylamide andlithium diisopropylamide; metal hydrides such as lithium hydride andsodium hydride; metal alkoxides having 1 to 6 carbon atoms, such aslithium ethoxide, lithium tert-butoxide, sodium methoxide, sodiumethoxide and potassium tert-butoxide; amides-such as lithium amide,potassium amide and sodium amide; inorganic bases such as lithiumhydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate,potassium carbonate and sodium hydrogen carbonate; and tertiary aminessuch as triethylamine, tri(n-propyl)amine, tri(n-butyl)amine,diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine,γ-collidine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine and N-methylmorpholine. The reaction is carried outusing 1 to 5 mol, preferably 1 to 3 mol, of compound (IV) per mol ofcompound (III). Reaction temperature is normally about −80 to 100° C.,preferably −50 to 60° C. Reaction time is normally 1 minute to 72 hours,preferably 15 minutes to 24 hours, depending on the kinds of compounds(III) and (IV), the kind of solvent, reaction temperature etc.

In the above formulas, R⁷ represents hydrogen or a lower alkyl group; R⁸represents hydrogen or a hydroxyl group-protecting group; the othersymbols have the same definitions as those shown above.

The lower alkyl group represented by R⁷ is exemplified by the same loweralkyl groups as those mentioned to exemplify the lower alkyl group usedfor R⁶ in method A.

The hydroxyl group-protecting group represented by R⁸ may be any one, aslong as it does not interfere with the reaction; preferable examplesthereof include ether-forming protecting groups such as methoxymethyl,benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2-tetrahydropyranyl,4-methoxy-4-tetrahydropyranyl, 2-tetrahydrofranyl, benzyl,p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl and trityl; silylether-forming protecting groups such as trimethylsilyl, triethylsilyl,triisopropylsilyl, isopropyldimethylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,triphenylsilyl and methyldiphenylsilyl; and ester-forming protectinggroups such as formyl, acetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, pivaloyl and benzoyl.

When R⁸ in formula (V) is hydrogen, compound (V) or a salt thereof isreacted with compound (VI). The salt of compound (V) is exemplified byacid adduct salts with the acids mentioned to exemplify acids that forman acid adduct salt with compound (I). This reaction is normally carriedout in a solvent and, if necessary, in the presence of a base. Suchsolvents and bases are identical to the solvents and bases mentioned formethod A above. The reaction is carried out using 1 to 10 mol,preferably 1 to 5 mol, of compound (VI) per mol of compound (V) or saltthereof. Reaction temperature is normally about −30 to 200° C.,preferably −10 to 150° C. Reaction time is normally 1 minute to 120hours, preferably 15 minutes to 48 hours, depending on the kinds ofcompounds (V) and (VI), the kinds of solvent and base, reactiontemperature etc.

Compound (I) can also be produced by producing compound (VIII) fromcompounds (V) and (VII) and cyclizing compound (VIII). This methodinvolves the acylation of compound (VII) or a salt thereof with compound(V), a salt thereof or a reactive derivative thereof.

Specifically, free acid (V), a salt thereof (inorganic salt, organicsalt) or a reactive derivative thereof (e.g., acid halide, acid azide,acid anhydride, mixed acid anhydride, active amide, active ester, activethioester etc.) is subjected to acylation reaction. Inorganic saltsinclude alkali metal salts (e.g., sodium salt, potassium salt) andalkaline earth metal salts (e.g., calcium salt). Organic salts include,for example, trimethylamine salt, triethylamine salt,tert-butyldimethylamine salt, dibenzylmethylamine salt,benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt andquinoline salt. Acid halides include, for example, acid chloride andacid bromide. Mixed acid anhydrides include mono-C₁₋₄ alkylcarbonic acidmixed acid anhydrides (e.g., mixed acid anhydrides of free acid (V) andmonomethylcarbonic acid, monoethylcarbonic acid, monoisopropylcarbonicacid, monoisobutylcarbonic acid, mono-tert-butylcarbonic acid,monobenzylcarbonic acid, mono(p-nitrobenzyl)carbonic acid,monoallylcarbonic acid etc.), C₁₋₆ aliphatic carboxylic acid mixed acidanhydrides (e.g., mixed acid anhydrides of free acid (V) and aceticacid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid,trichloroacetic acid, acetoacetic acid etc.), C₇₋₁₁ aromatic carboxylicacid mixed acid anhydrides (e.g., mixed acid anhydrides of free acid (V)and benzoic acid, p-toluic acid, p-chlorobenzoic acid etc.) and organicsulfonic acid mixed acid anhydrides (e.g., mixed acid anhydrides withmethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid etc.). Active amides include amides withnitrogen-containing heterocyclic compounds [e.g., acid amides of freeacid (V) and pyrazole, imidazole, benzotriazole etc.; thesenitrogen-containing heterocyclic compounds may be substituted for byC₁₋₄ alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl), C₁₋₆ alkoxys (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy), halogen atoms (e.g., fluorine,chlorine, bromine), oxo, thioxo, C₁₋₆ alkylthios (e.g., methylthio,ethylthio, propylthio, butylthio) etc.].

Active esters include, for example, organic phosphoric acid esters(e.g., diethoxyphosphoric acid esters, diphenoxyphosphoric acid esters),p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,pentachlorophenyl ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester,6-chloro-1-hydroxybenzotriazole ester and 1-hydroxy-1H-2-pyridone ester.Active thioesters include esters with aromatic heterocyclic thiolcompounds [their heterocyclic rings may be substituted for by C₁₋₄alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl), C₁₋₆ alkoxys (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy), halogen atoms (e.g., fluorine,chlorine, bromine), C₁₋₆ alkylthios (e.g., methylthio, ethylthio,propylthio, butylthio) etc.] [e.g., 2-pyridylthiol ester,2-benzothiazolylthiol ester].

The salt of compound (VII) is exemplified by salts with alkali metals(e.g., potassium, sodium, lithium), salts with alkaline earth metals(e.g., calcium, magnesium) and acid addition salts (acid adduct saltswith the acids mentioned to exemplify acids that form an acid additionsalt with compound (I)).

This reaction is normally carried in a solvent; a solvent that does notinterfere with the reaction is chosen as appropriate. Such solventsinclude, for example, ethers such as dioxane, tetrahydrofuran, diethylether, tert-butyl methyl ether, diisopropyl ether and ethyleneglycoldimethyl ether; esters such as ethyl formate, ethyl acetate andbutyl acetate; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane;hydrocarbons such as n-hexane, benzene and toluene; amides such asformamide, N,N-dimethylformamide and N,N-dimethylacetamide; ketones suchas acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrilessuch as acetonitrile and propionitrile; dimethyl sulfoxide, sulfolane,hexamethylphosphoramide and water; these solvents are used as simple ormixed solvents. The amount of compound (VII) used is normally 1 to 10mol, preferably 1 to 5 mol, per mol of compound (V). The reaction isnormally carried out in the temperature range from −80 to 200° C.,preferably from −40 to 150° C., and most preferably from −30 to 100° C.Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to24 hours, depending on the kinds of compounds (V) and (VII), the kind ofsolvent (also mixing ratio in the case of a mixed solvent), reactiontemperature etc. When compound (V) is used as an acid halide, thereaction can be carried out in the presence of a deoxidizer to removethe released hydrogen halide from the reaction system. Such deoxidizersinclude, for example, inorganic bases such as sodium carbonate,potassium carbonate, calcium carbonate and sodium hydrogen carbonate;tertiary amines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, pyridine, lutidine, γ-collidine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine andN-methylmorpholine; and alkylene oxides such as propylene oxide andepichlorohydrin.

Compound (VIII) can be then cyclized to yield compound (I) after thehydroxyl group-protecting group R⁸ is removed as necessary. Depending onthe kind of protecting group, this deprotection reaction can be carriedout by a known method chosen as appropriate. For example, deprotectioncan be achieved with an acid (e.g., formic acid, acetic acid, propionicacid, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoricacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid)or by catalytic reduction [Raney nickel, platinum, palladium, rhodium,or the like, for example, used as a catalyst at normal pressure orincreased pressure (2 to 100 atm)] in the case of ether-formingprotecting groups, with one of the above-mentioned acids or a Lewis acid(e.g., zinc chloride, zinc bromide, aluminum chloride, titaniumchloride) or a fluoride (e.g., potassium fluoride, sodium fluoride,tetraethylammonium fluoride, tetra-n-butylammonium fluoride) in the caseof silyl ether-forming protecting groups, or with a base (e.g.,potassium hydrogen carbonate, sodium hydrogen carbonate, potassiumcarbonate, sodium carbonate, lithium hydroxide, potassium hydroxide,sodium hydroxide) in the case of ester-forming protecting groups. Thereaction is normally carried out in a solvent; such solvents areexemplified by the solvents used for method A.

In the case of ether-forming protecting groups or silyl ether-formingprotecting groups, the amount of acid or Lewis acid used is normally0.001 to 100 mol, preferably 0.01 to 50 mol, per mol of compound (V).Reaction temperature is normally −50 to 150° C., preferably −20 to 100°C. Reaction time is normally 1 minute to 72 hours, preferably 15 minutesto 48 hours.

In the case of ester-forming protecting groups, the amount of base usedis normally 0.01 to 50 mol, preferably 0.1 to 20 mol, per mol ofcompound (V). Reaction temperature is normally −20 to 150° C.,preferably −10 to 100° C. Reaction time is normally 1 minute to 72hours, preferably 15 minutes to 48 hours.

Compound (VIII) thus deprotected is cyclized to compound (I). Thisreaction is normally carried out in a solvent. Such solvents areexemplified by the solvents used for method A. Reaction temperature isnormally −10 to 200° C., preferably −5 to 150° C. In this reaction, abase may be used as a catalyst; such bases are exemplified by the basesused for method A. To promote the reaction, there may be used, forexample, 2-chloro-3-methylbenzoxazolium tetrafluoroborate,2-chloro-3-ethylbenzoxazolium tetrafluoroborate,2-chloro-3-methylbenzothiazolium tetrafluoroborate,2-chloro-3-ethylbenzothiazolium fluoroborate,2-chloro-1-methylpyridinium tetrafluoroborate and2-chloro-1-ethylpyridinium tetrafluoroborate. The amount of reactionpromoter used is normally 1 to 10 mol, preferably 1 to 3 mol, per mol ofcompound (VIII). A base is also used when a reaction promoter is used.Such bases are exemplified by the bases used for method A. Reactiontemperature is normally −30 to 150° C., preferably −20 to 100° C.Reaction time is normally 1 minute to 72 hours, preferably 15 minutes to48 hours.

When one of R³ and R⁴ is an acyl group, an esterified carboxyl group ora carbamoyl group that may have a substituent, compound (I) can beproduced by methods C, D and E below.

Of the compounds of formula (I), compound (Ib), which has an acyl groupfor R³ or R⁴, can be produced by method C.

In these formulas, R^(4a) represents an acyl group; R^(4b) represents agroup resulting from removal of the carbonyl group or sulfonyl groupfrom an acyl group; the other symbols have the same definitions as thoseshown above.

The acyl group represented by R^(4a) means an acyl group represented byR⁴; the “acyl group” in the “group resulting from removal of thecarbonyl group or sulfonyl group from an acyl group” represented byR^(4b) means an acyl group represented by R⁴.

In this reaction, compound (Ia) or a salt thereof can be acylated withcompound (IX) or (X) or a reactive derivative thereof to yield compound(Ib). The salt of compound (Ia) is exemplified by the same acid adductsalts as those mentioned to exemplify the salt of compound (I). Thereactive derivative of compound (IX) is exemplified by the reactivederivatives mentioned for method B. The reactive derivative of compound(X) is exemplified by sulfonic acid halides (e.g., sulfonyl bromide,sulfonyl chloride) and sulfonic anhydride; the reaction is carried outby the method described for method B or a modification thereof.

In the compounds of formula (I), compound (Ic), which has an esterifiedcarboxyl group for R⁴, can be produced by method D.

In these formulas, R^(4c) represents an esterified carboxyl group; Qrepresents a halogen atom; the other symbols have the same definitionsas those shown above.

R^(4c) is any one of the carboxyl groups that may be esterified,represented by R⁴, except the free carboxyl group.

The halogen represented by Q is exemplified by fluorine, chlorine,bromine and iodine. This reaction is carried out by reacting compound(Ia) or a salt thereof and compound (XI). The salt of compound (Ia) isexemplified by the acid adduct salts mentioned to exemplify the acidadduct salt of compound (Ia) for reaction D above. This reaction isnormally carried out in a solvent; such solvents are exemplified by thesolvents used for method B. In this reaction, a hydrogen halide isreleased. To remove the hydrogen halide, the reaction can be carried outin the presence of an acid scavenger. Such acid scavenger includes, forexample, inorganic bases such as sodium carbonate, potassium carbonate,calcium carbonate and sodium hydrogen carbonate; tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,pyridine, lutidine, γ-collidine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine; andalkylene oxides such as propylene oxide and epichlorohydrin.

The amount of compound (XI) used is normally 1 to 20 mol, preferably 1to 10 mol, per mol of compound (Ia). Reaction temperature is normally−30 to 120° C., preferably −20 to 80° C. Reaction time is normally 1minute to 72 hours, preferably 15 minutes to 48 hours.

Of the compounds of formula (I), compound (Id), which has a carbamoylgroup which may be substituted, can be produced by method E.

In these formulas, R^(4d) represents a carbamoyl group which may besubstituted; R⁹, R¹⁰ and R¹¹, whether identical or not, representhydrogen or one of the substituents mentioned to exemplify thesubstituent for the carbamoyl group represented by R⁴, which may besubstituted; the other symbols have the same definitions as those shownabove.

In this method, compound (Ic) or a salt thereof can be reacted withcompound (XII) to yield compound (Id). The salt of compound (Ic) isexemplified by the same acid addition salts as those mentioned toexemplify the salt of compound (I). This reaction is normally carriedout in a solvent; such solvents are exemplified by the solvents used formethod A. The amount of compound (XII) used is normally 1 to 100 mol,preferably 1 to 30 mol, per mol of compound (Ic). Reaction temperatureis normally −30 to 200° C., preferably −10 to 100° C. Reaction time isnormally 1 minute to 72 hours, preferably 15 minutes to 48 hours.

Compound (Id) can also be produced by reacting compound (Ia) withisocyanate derivative (XIII). The reaction is normally carried out in asolvent. Said solvent may be any one, as long as it does not interferewith the reaction. For example, ethers such as dioxane, tetrahydrofuran,diethyl ether, tert-butyl ether, diisopropyl ether and ethyleneglycol-dimethyl ether; esters such as ethyl formate, ethyl acetate andn-butyl acetate; halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, trichlene and 1,2-dichloroethane;hydrocarbons such as n-hexane, benzene and toluene; amides such asformamide, N,N-dimethylformamide and N,N-dimethylacetamide; ketones suchas acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrilessuch as acetonitrile and propionitrile; dimethyl sulfoxide, sulfolane,hexamethylphosphoramide are used as simple or mixed solvents.

The amount of compound (XIII) used is normally 1 to 30 mol, preferably 1to 15 mol, per mol of compound (Ia). Reaction temperature is normally−20 to 150° C., preferably −10 to 100° C. Reaction time is normally 1minute to 72 hours, preferably 15 minutes to 48 hours.

In these formulas, R¹² represents hydrogen, a lower alkyl group, acycloalkyl group, an aralkyl group or an acyl group; R¹³ and R¹⁴,whether identical or not, represent hydrogen or a lower alkyl group; R¹⁵represents hydrogen, a lower alkyl group or an aralkyl group; R¹⁶represents a lower alkyl group or an aryl group; the other symbols havethe same definitions as those shown above. The lower alkyl grouprepresented by R¹² in formula (XIV) is exemplified by alkyl groupshaving 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, with preferencegiven to those having 1 to 4 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl and isobutyl. The cycloalkyl group representedby R¹²is exemplified by cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl, with preference given tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aralkyl grouprepresented by R¹² is exemplified by benzyl, phenethyl and phenylpropyl.

The acyl group represented by R¹² is exemplified by aliphatic acylgroups such as alkanoyl groups, alkenoyl groups, cycloalkanecarbonylgroups and alkanesulfonyl groups; aromatic acyl groups such as aroylgroups, arylalkanoyl groups, arylalkenoyl groups and arenesulfonylgroups; heterocyclic aromatic acyl groups such as aromatic heterocycliccarbonyl groups and aromatic heterocyclic alkanoyl groups; andnon-aromatic heterocyclic carbonyl groups (aliphatic heterocycliccarbonyl groups).

“Alkanoyl groups” mean alkylcarbonyl groups, preferable examples thereofincluding lower alkanoyl groups having 1 to 8 carbon atoms, such asformyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl and hexanoyl.

“Alkenoyl groups” mean alkenylcarbonyl groups preferable examplesthereof including C₃₋₆ alkenoyl groups such as acryloyl, methacryloyl,crotonoyl and isocrotonoyl.

“Cycloalkanecarbonyl groups” mean cycloalkylcarbonyl groups, preferableexamples thereof including those having 4 to 7 carbon atoms, such ascyclopropanecarbonyl groups, cyclobutanecarbonyl groups,cyclopentanecarbonyl groups and cyclohexanecarbonyl groups.

“Alkanesulfonyl groups” mean alkylsulfonyl groups, preferable examplesthereof including those having 1 to 4 carbon atoms, such as mesyl,ethanesulfonyl and propanesulfonyl.

“Aroyl groups” mean arylcarbonyl groups, preferable examples thereofincluding those having 7 to 11 carbon atoms, such as benzoyl, p-toluoyl,1-naphthoyl and 2-naphthoyl.

“Arylalkanoyl groups” mean alkylcarbonyl groups substituted for by anaryl group, preferable examples thereof including C₆₋₈ aryl-C₂₋₅alkanoyl groups such as phenylacetyl, phenylpropionyl, hydroatropoyl andphenylbutyryl.

“Arylalkenoyl groups” mean alkenylcarbonyl groups substituted for by anaryl group, preferable examples thereof including C₆₋₈ aryl-C₃₋₅alkenoyl groups such as cinnamoyl and atropoyl.

“Arenesulfonyl groups” mean arylsulfonyl groups, preferable examplesthereof including those having 6 to 8 carbon atoms, such asbenzenesulfonyl and p-toluenesulfonyl.

Preferable examples of “aromatic heterocyclic carbonyl groups” includefuroyl, thenoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl,oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl andpyrazolecarbonyl.

“Aromatic heterocyclic alkanoyl groups” mean alkylcarbonyl groupssubstituted for by an aromatic heterocyclic group, preferable examplesthereof including aromatic heterocyclic ring-C₂₋₅ alkanoyl groups suchas thienylacetyl, thienylpropanoyl, furylacetyl, thiazolylacetyl,1,2,4-thiadiazolylacetyl and pyridylacetyl.

Preferable examples of “non-aromatic heterocyclic carbonyl groups”include aliphatic heterocyclic carbonyls such as azetidinylcarbonyl,pyrrolidinylcarbonyl and piperidinylcarbonyl.

The lower alkyl group represented by R¹³, R¹⁴, R¹⁵ or R¹⁶ in formulas(XIV), (XV) and (XVI) is exemplified by lower alkyl groups representedby R¹². The aralkyl group represented by R¹⁵ is exemplified by aralkylgroups represented by R¹². The aryl group represented by R¹⁶ isexemplified by phenyl, naphthyl, anthryl, phenanthryl andacenaphthylenyl groups, with preference given to phenyl and naphthyl.These aryl groups may have 1 to 5 substituents. Such substituentsinclude alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl,propyl), alkoxy groups having 1 to 3 carbon atoms (e.g., methoxy,ethoxy, propoxy) and halogen atoms (e.g., fluorine, chlorine, bromine,iodine).

In this method, compounds (XIV) and (XV) are reacted in the presence ofcompound (XVI) to yield compound (XVII).

This reaction is normally carried out in a solvent; a solvent that doesnot interfere with the reaction is chosen as appropriate. Such solventsinclude, for example, alcohols such as methanol, ethanol, propanol,isopropanol, butanol and tert-butanol; ethers such as dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether and ethylene glycol-dimethyl ether; esters such as ethyl formate,ethyl acetate and n-butyl acetate; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, trichlene and1,2-dichloroethane; hydrocarbons such as n-hexane, benzene and toluene;amides such as formamide, N,N-dimethylformamide andN,N-dimethylacetamide; ketones such as acetone, methyl ethyl ketone andmethyl isobutyl ketone; nitriles such as acetonitrile and propionitrile;dimethyl sulfoxide, sulfolane, hexamethylphosphoramide and water; thesesolvents are used as simple or mixed solvents.

Reaction temperature is normally −80 to 150° C., preferably −50 to 120°C. The amount of each of compounds (XV) and (XVI) used is normally 1 to5 mol, preferably 1 to 3 mol, per mol of compound (XIV).

The ester of compound (XVII) is then subjected to hydrolysis,hydrogenolysis, or the like, to yield compound (XVIII).

This hydrogenolysis reaction is normally carried out in a solvent; asolvent that does not interfere with the reaction is chosen asappropriate. Such solvents include, for example, alcohols such asmethanol, ethanol, propanol, isopropanol, butanol and tert-butanol;ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether and ethylene glycol-dimethyl ether;halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, trichlene and 1,2-dichloroethane; hydrocarbons such asn-hexane, benzene and toluene; amides such as formamide,N,N-dimethylformamide and N,N-dimethylacetamide; ketones such asacetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles suchas acetonitrile and propionitrile; dimethyl sulfoxide, sulfolane,hexamethylphosphoramide and water; these solvents are used as simple ormixed solvents.

This reaction is carried out in the presence of a base. Preferably usedbases include metal hydroxides such as lithium hydroxide, potassiumhydroxide, sodium hydroxide and barium hydroxide, and metal carbonatessuch as potassium carbonate, sodium carbonate and barium carbonate. Theamount of base used is normally 1 to 30 mol, preferably 1 to 10 mol, permol of compound (XVII). Reaction temperature is normally −30 to 150° C.,preferably −10 to 120° C. Reaction time is normally 15 minutes to 48hours, preferably 30 minutes to 24 hours.

When compound (XVIII) is produced by a hydrogenolysis reaction, thereaction is normally carried out using a catalyst. This catalyst ispreferably one for catalytic reduction reaction, exemplified by platinumcatalysts (e.g., platinum oxide, platinum black, platinum-carbon),palladium catalysts (e.g., palladium chloride, palladium-carbon,palladium-calcium carbonate, palladium-barium sulfate), rhodiumcatalysts (e.g., rhodium-carbon, rhodium-alumina) and rutheniumcatalysts (e.g., ruthenium oxide, ruthenium-carbon), with greaterpreference given to palladium catalysts. The reaction is normallycarried out in a solvent; a solvent that does not interfere with thereaction is chosen as appropriate. Such solvents include, for example,alcohols such as methanol, ethanol, propanol, isopropanol, butanol andtert-butanol; ethers such as dioxane, tetrahydrofuran, diethyl ether,tert-butyl methyl ether, diisopropyl ether and ethylene glycol-dimethylether; esters such as ethyl formate, ethyl acetate and n-butyl acetate;hydrocarbons such as n-hexane, benzene and toluene; amides such asformamide, N,N-dimethylformamide and N,N-dimethylacetamide; and water;these solvents are used as simple or mixed solvents.

Reaction temperature is normally −10 to 120° C., preferably 0 to 100° C.Although this reaction is normally carried out at normal pressure, itmay be carried out at increased pressure in some cases. Such pressure ispreferably 1 to 200 atm.

Compound (XVIII) can be decarbonized by heating to yield compound (I).This reaction is normally carried out in a solvent; a solvent that doesnot interfere with the reaction is chosen as appropriate. Such solventsinclude, for example, alcohols such as methanol, ethanol, propanol,isopropanol, butanol and tert-butanol; ethers such as dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether and ethylene glycol-dimethyl ether; esters such as ethyl formate,ethyl acetate and n-butyl acetate; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, trichlene and1,2-dichloroethane; hydrocarbons such as n-hexane, benzene and toluene;amides such as formamide, N,N-dimethylformamide andN,N-dimethylacetamide; ketones such as acetone,. methyl ethyl ketone andmethyl isobutyl ketone; nitriles such as acetonitrile and propionitrile;dimethyl sulfoxide, sulfolane, hexamethylphosphoramide and water;

these solvents are used as simple or mixed solvents.

Reaction temperature is normally 0 to 180° C., preferably 10 to 150° C.Reaction time is normally 5 minutes to 24 hours, preferably 10 minutesto 12 hours.

When a compound involved in each reaction described above has an aminogroup, a carboxyl group or a hydroxyl group as a substituent, the groupmay incorporate a protecting group in common use in peptide chemistryand other fields; the desired compound can be obtained by removing theprotecting group as necessary after reaction.

Useful amino group-protecting groups include, for example, formyl group,C₁₋₆ alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl), benzyl group,tert-butyloxycarbonyl group, benzyloxycarbonyl group,9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group,phenylcarbonyl group, C₁₋₆ alkyloxycarbonyl groups (e.g.,methoxycarbonyl, ethoxycarbonyl), C₇₋₁₀ aralkylcarbonyl groups (e.g.,benzylcarbonyl), trityl group, phthaloyl group andN,N-dimethylaminomethylene group. These groups may be substituted by 1to 3 halogen atoms (e.g., fluorine, chlorine, bromine), nitro group etc.

Useful carboxyl group-protecting groups include C₁₋₆ alkyl groups (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl group,silyl group, benzyl group and allyl group. These groups may besubstituted for by 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine), nitro group etc.

Useful hydroxyl group-protecting groups include methoxymethyl group,allyl group, tert-butyl group, C₇₋₁₀ aralkyl groups (e.g., benzyl),formyl group, C₁₋₆ alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl),benzoyl group, C₇₋₁₀ aralkylcarbonyl groups (e.g., benzylcarbonyl),pyranyl group, furanyl group and trialkylsilyl groups. These groups maybe substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine), C₁₋₆ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl,butyl, tert-butyl), phenyl group, C₇₋₁₀ aralkyl groups (e.g., benzyl),nitro group etc.

These protecting groups can be removed by commonly known methods ormodifications thereof, including those using acids, bases, reduction,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateetc.

When a compound is obtained in a free form by each of theabove-described reactions of the present invention, it may be convertedto a salt by a conventional method; when it is obtained as a salt, itmay be converted to a free form or another salt by a conventionalmethod.

Compound (I) thus obtained can be isolated and purified from thereaction mixture by commonly known means such as extraction,concentration, neutralization, filtration, recrystallization, columnchromatography and thin-layer chromatography.

A salt of compound (I) can be produced by, for example, adding one ofthe above-described inorganic acids or organic acids to compound (I) bya commonly known means. Compounds (III) and (IV), used as startingcompounds in method A above, can be produced by, for example, the methoddescribed in U.S. Pat. No. 4,584,385 or a method based thereon.

Compound (V), used as a starting compound in method B above, can beproduced by, for example, the method described in the Journal ofMedicinal Chemistry, 21, 82 (1978) or Chemistry Letters, 166 (1980) or amethod based thereon; compound (VI) can be produced by, for example, themethod described in the Journal of Organic Chemistry, 42, 3608 (1977) ora method based thereon; compound (VII) can be produced by the methoddescribed in the Journal of the Chemical Society, 95, 132 (1909) or amethod based thereon.

In addition to the above-mentioned processes, compound (I) can also beproduced by the method described in U.S. Pat. No. 4,584,385 or a methodbased thereon.

Although compound (I) can be produced by chemical processes as describedabove, it can also be produced using microorganisms. Of the compounds offormula (I), indolmycin, can be produced by, for example, the methodsdescribed in the literature [K. V. Rao, Antibiotics and Chemotherapy(Washington, D.C.), 10, 312 (1960); W. S. Marsh et al., ibid., 10, 316(1960); Schach von Wittenau, M. et al., J. Am. Chem. Soc. 83, 4678(1961), ibid., 85, 3425 (1963)], using as producer strains Streptomycesgriseus subsp. griseus ATCC 1264 (American Type Culture CollectionCatalogue of Bacteria & Bacteriophages, 18th edition, 1992) etc.Streptomyces sp. HC-21, a new strain, can also be used as a producerstrain.

The microorganism used for the method of indolmycin production of thepresent invention is the Streptomyces sp. HC-21 strain (hereinafter alsoreferred to as “HC-21 strain”) isolated from a soil sample fromTenninkyo, Asahikawa-shi, Hokkaido, Japan.

According to the method described in the International Journal ofSystematic Bacteriology, 16(3), 313-340 (1960), the HC-21 strain ischaracterized as follows: All findings on medium were obtained during 14days of cultivation and observation at 28° C., unless otherwise stated.

(I) Morphological characteristics

The aerial mycelia elongate in simple branches from well elongated andbranched substrate mycelia, with gently waved or key-shaped spore chains(normally 10 to 50 spores or more) on their tips. No whirls are noted.Spores are cylindrical (1.1 to 1.2×1.4 to 1.5 μm) and have a spinysurface.

(II) Nature in culture

Degree of growth (G), growth and color tone of aerial mycelia (AM), backface color tone (R), presence or absence and color tone of solublepigment (SP) etc. on various media are described below. For thedescription of color, standard color tone symbols in parentheses arebased on the Color Harmony Manual of Container Corporation of America,4th edition, 1958.

TABLE 1 (a) Sucrose-nitrate- G Poor, light ivory (2ca) agar medium AMNone R Light ivory (2ca) SP None (b) Glucose-aspara- G Good, ivory (2ea)gine-agar medium AM Good, ivory (2ea) R Light yellowish brown (2ia) toyellowish brown (3na) SP None (c) Glycerol-aspara- G Good, yellowishbrown (3ic) gine-agar medium AM Good, Light yellowish gray (2gc) RYellowish brown (31a) to brown (41a) SP None (d) Starch-inorganic GModerate, ivory (2ec) salt-agar medium AM Moderate, light greenish gray(2cb) R Light yellowish brown (2ga) to light yellowish gray (2gc) SPNone (e) Tyrosine-agar me- G Good, light yellowish brown (2ga) dium AMIvory (2ea) R Light yellowish brown (21a) to yellowish brown (31c) SPNone (f) Enriched agar me- G Moderate, light grayish reddish brown dium(5ic) AM Poor, white R Light grayish brown (4ga) to reddish brown (61a)SP None (g) Yeast extract-malt G Good, yellowish brown (4ia)extract-agar me- AM Moderate, light grayish brown (5ga) to dium grayishyellowish brown (4ge) R Yellowish brown (3ia) to reddish yellowish brown(5pa) SP None (h) oatmeal-agar me- G Good, light grayish brown (4gc)dium AM Moderate, light reddish white (5ea) to grayish brown (5gc) RBright reddish brown (6ia) to grayish brown (5gc) SP None (i)Peptone-yeast G Moderate, ivory (2ea), localized extract-iron-agar AMNone medium R Light yellowish brown (2ga) to yellowish grayish brown(3ia) SP None (III) Physiological nature (a) Growth temperature range 11to 29° C. Optimal growth temperature range 18 to 24° C. (b) Nitratereduction Weakly positive (c) Gelatin liquefaction Negative(glucose-peptone-gelatin medium) (d) Starch hydrolysis Negative (e)Defatted milk coagulation Negative Defatted milk peptonization Negative(f) Melanin-like pigment formation Tyrosine-agar medium NegativePeptone-yeast extract- Negative iron-agar medium (g) Carbon sourceassimilation (agar medium containing pridham and gottlieb) L-arabinose −D-xylose − D-glucose ++ D-fructose + Sucrose − Inositol − L-rhamnose ++Raffinose − D-mannitol − Control − (Note) ++: relatively good growth +:growth noted ±: + or − indeterminable −: no growth

(IV) Cell analysis

Analysis in accordance with the method of Hasegawa et al. [Journal ofGeneral Applied Microbiology 29, 319-322 (1983)] identified thediaminopimelic acid in the hydrochloric acid hydrolyzate of cells as theLL-configuration.

Judging from the results shown above, specifically the light yellowishbrown to grayish brown aerial mycelia, gently waved or key-shaped sporechains, spiny spore surfaces, diaminopimelic acid in theLL-configuration, and other findings, it is evident that this strainbelongs to the genus Streptomyces; the strain was designatedStreptomyces sp. HC-21.

The Streptomyces sp. HC-21 strain as such is characterized by thecapability of L-rhamnose assimilation and spiny spore surfaces.

The Streptomyces sp. HC-21 strain as such has been deposited underaccession number IFO-15984 at the Institute for Fermentation, Osaka(foundation), since Jun. 12, 1996, and under accession number FERMBP-5571 at the National Institute of Bioscience and Human-Technology,Agency of Industrial Science and Technology, Ministry of InternationalTrade and Industry of the Japan (1-3, Higashi 1-chome, Yatabe, TsukubaCity, Ibaraki Prefecture), since Jun. 25, 1996.

The bacteria of the genus Streptomyces can undergo variation, naturallyor by mutagens, as a general nature of microorganisms. Even the variousvariants obtained by, for example, irradiation with radiations such as Xrays, gamma rays and ultraviolet rays, single spore separation,treatment with various chemicals, cultivation on drug-containing media,and other means, or naturally-occurring mutants, are all usable for themethod of the present invention, as long as they are capable ofproducing indolmycin.

Although the culture medium for the method of the present invention maybe liquid or solid, as long as it contains nutrient sources usable bythe strain used, a liquid medium is preferred for large-scale treatment.The medium is supplemented as appropriate with assimilable nutrientsources, digestible nitrogen sources, inorganic substances, and tracenutrients.

Carbon sources include, for example, glucose, lactose, sucrose, maltose,dextrin, starch, glycerol, mannitol, sorbitol, oils and fats (e.g.,soybean oil, olive oil, rice bran oil, sesame oil, lard oil, chickenoil); nitrogen sources include, for example, meat extract, yeastextract, dry yeasts, soybean flour, corn steep liquor, peptone,cottonseed flour, blackstrap molasses, urea, ammonium salts (e.g.,ammonium sulfate, ammonium chloride, ammonium nitrate, ammonium acetate)and others. Also used as appropriate are salts containing sodium,potassium, calcium, magnesium etc., metal salts such as those of iron,manganese, zinc, cobalt, nickel etc., salts of phosphoric acid, boricacid etc., and salts of organic acids such as acetic acid and propionicacid. Additionally, amino acids (e.g., glutamic acid, aspartic acid,alanine, lysine, valine, methionine, proline), vitamins (e.g., B₁, B₂,nicotinic acid, B₁₂, C), nucleic acids (e.g. purine, pyrimidine andderivatives thereof) etc. may be contained. It is of course commonpractice to add inorganic or organic acids, alkalis, buffers etc. forregulation of the medium's pH, and appropriate amounts of oils and fats,surfactants etc. for defoaming.

Cultivation may be achieved by standing culture, shaking culture,spinner culture, or the like. For large-scale treatment, submergedspinner culture is of course desirable.

Although culturing conditions vary depending on the condition andcomposition of the medium, the kind of strain, and the means ofcultivation, it is normally recommended that temperature and initial pHbe 15 to 26° C. and about 5 to 9, respectively. It is desirable thattemperature in the middle stage of cultivation and initial pH be 20 to25° C. and about 6 to 8, respectively. Duration of cultivation alsovaries depending on the above-mentioned conditions but it is recommendedthat cultivation be continued until the concentration of the desiredbioactive substance reaches maximum. It normally takes about 1 to 10days in the case of shaking culture or spinner culture using a liquidmedium.

The resulting bioactive substance indolmycin can be extracted andpurified from the culture on the basis of its chemical nature.

Because indolmycin is produced in the culture broth and cells, it can bepurified by separating the culture broth and cells by filtration orcentrifugation from the culture, extracting it from the resultingfiltrate or centrifugal supernatant using an organic solvent, orextracting it from cells using an organic solvent, and isolating it fromeach extract or the combined extract.

For industrial purposes, it is advantageous to purify indolmycin fromthe extract obtained by adding an organic solvent such as methanol,acetone, butanol or ethyl acetate directly to the culture, with the cellseparation operation omitted.

Because indolmycin is a weakly basic oil-soluble substance, itscollection from the culture broth permits the use of means of separationand purification in common use for collection of related microbialmetabolites. For example, methods based on solubility differences fromimpurity substances and chromatographies using various carriers such asactivated charcoal nonionic high porous resin, silica gel, alumina anddextran gel can be used singly or in combination.

The method of isolating and collecting indolmycin from the culture ishereinafter described specifically. First, cells are removed byfiltration from the culture broth; the resulting supernatant is adjustedto appropriate pH; a solvent such as ethyl acetate is added, followed byvigorous stirring, to yield an ethyl acetate layer. The organic layerobtained is sequentially washed with alkali, acid and water, after whichit is concentrated; the resulting concentrate is subjected to silica gelcolumn chromatography. Useful developing solvents include, for example,chloroform-methanol or hexane-acetone mixed solvents. After theeffective fractions are combined and concentrated, the concentrate issubjected to Sephadex LH-20 chromatography. Useful developing solventsare methanol and mixed solvents such as hexane-toluene-methanol andhexane-methylene chloride-methanol. Aft er concentration, the eluatecontaining the effective fractions is purified by preparative highperformance liquid chromatography. The column packing used here isODS-SH343 S-15 (produced by Yamamura Kagaku Kenkyujo); the solventsystem used is a combination of 0.02 M phosphate buffer (pH 6.3) and 26%CH₃CN.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is hereinafter described in more detail by meansof, but not limited to, the following working examples, experimentalexamples and preparation example. In the description below, “roomtemperature” means about 15 to 30° C.

EXAMPLES Example 1

A platinum loopful of Streptomyces sp. HC-21 strain, previouslysufficiently grown on a slant medium consisting of yeast extract-maltoseextract-agar, was inoculated to a sterile 2 l Sakaguchi flask containing500 ml of a seed medium of pH 7.0 consisting of 2% glucose, 3% solublestarch, 1% corn steep liquor, 1% fresh soybean flour, 0.5% polypeptone,0.3% sodium chloride and 0.5% precipitating calcium carbonate, andcultured at 24° C. on a reciprocal shaker for 2 days. To this 500 mlculture broth was injected 120 l of a principal medium of pH 7.0consisting of 2.0% glucose, 3.0% soluble starch, 1.0% defatted soybeanflour, 0.3% corn steep liquor, 0.1% yeast extract, 0.5% polypeptone,0.2% oatmeal agar, 0.3% sodium chloride, 0.5% precipitating calciumcarbonate, 0.05% ACTCOL 31-56 (produced by Takeda Chemical Industries,Ltd., Japan) and 0.05% silicone, followed by transplantation to asterile 200 l fermentation jar and 90 hours of cultivation underconditions of 24° C. temperature, 1.1 kg/cm² internal pressure, 120l/min aeration rate and 120 rpm stirring rate.

The 120 l of the culture broth thus obtained was filtered using HyfloSuper Cel to yield 110 l of a filtrate. This filtrate was adjusted to pH3.0 with dilute sulfuric acid; an equal amount of ethyl acetate wasadded, followed by vigorous stirring, to yield 80 l of an ethyl acetatelayer. This ethyl acetate layer was washed with 30 l of a 2% NaHCO₃solution, then with 30 l of a 0.02 N.HCl solution, and thoroughly washedwith water, after which it was concentrated under reduced pressure toyield about 30 g of a concentrate. This concentrate was passed through asilica gel column (0.8 l) to adsorb the active ingredient, followed bysequential elution with 4 l of hexane-acetone (80:20), 4 l ofhexane-acetone (50:50) and 4 l of hexane-acetone (20:80). The effectivefractions were combined and concentrated under reduced pressure to yield1.53 g of a concentrate. This concentrate was dissolved in methanol; theresulting solution was passed through a column (2 l) of Sephadex LH-20(produced by Pharmacia, Sweden), thoroughly washed previously; theeffective eluted fractions from 1.3 l to 1.7 l were combined andconcentrated under reduced pressure to yield 490 mg of a powder. Thispowder was further developed (20 ml/min, 20 ml fractions) with a solventsystem of 0.02 M phosphate buffer (pH 6.3) and 26% CH₃CN, usingpreparative liquid chromatography (Hitachi model L-6250, detectorL-4000, YMC-Pack, ODS SH343 S-15 120 A, 214 nm), to yield effectivefractions (fraction Nos. 30 through 39). After the CH₃CN was removed,the effective fractions were washed with water and again extracted withethyl acetate; the ethyl acetate layer was concentrated under reducedpressure to yield 315 mg of crystalline indolmycin.

Elemental analysis (for C₁₄H₁₅N₃O₂): Calculated: C, 65.35; H, 5.88; N,16.33; Found : C, 65.14; H, 5.87; N, 16.07.

The physicochemical properties also agreed well with those ofindolmycin.

Example 2

(5S)-2-(N-benzyloxycarbonyl-N-methyl)amino-5[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

A solution of indolmycin (100 mg) in tetrahydrofuran (5 ml) was cooledto −30° C. To this cooled solution, triethylamine (0.217 ml) andcarbobenzoxychloride (0.167 ml) was subsequently added dropwise at −30°C. The whole was allowed to warm up to 0° C. and was stirred for 80minutes. Ethyl acetate was added to the reaction mixture. The mixturewas washed with water, saturated aqueous sodium hydrogen carbonatesolution and brine respectively and then the ethyl acetate solution wasdried over MgSO₄. Removal of the organic solvent gave a residue, whichwas recrystalized with isopropylether to afford the titled compound (115mg, 75.5%). m.p. 136-138° C.

IR (KBr) cm⁻¹: 3299, 1748 ¹H-NMR (CDCl₃) δ: 1.39(3H,d,J=7.2 Hz),3.34(3H,s), 3.81-3.93(1H,m), 5.10(1H,d,J=2.8 Hz), 5.31(2H,s),6.97-7.40(8H,m), 7.62(1H,d,J=7.4 Hz), 7.95(1H,bs).

Example 3

Following the same procedure as described in the Example 2, thefollowing compounds were prepared.

(5S)-2-(N-ethoxycarbonyl-N-methyl)amino-5[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3293, 1769, 1738. ¹H-NMR (CDCl₃) δ: 1.34(3H,d,J=7.0 Hz),1.41(3H,t,J=7.2 Hz), 3.32(3H,s), 3.88(1H,m), 4.35(2H,q,J=7.2 Hz),5.10(1H,d,J=2.6 Hz), 7.07-7.26(3H,m), 7.36(1H,d,J=8.2 Hz),7.67(1H,d,J=8.2 Hz), 8.15(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-isopropoxycarbonyl-N-methyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3272, 1732. ¹H-NMR (CDCl₃) δ: 1.36(6H,d,J=6.4 Hz),1.43(3H,d,J=7.4 Hz), 3.31(3H,s), 3.91(1H,m), 5.08(1H,m), 5.12(1H,d,J=2.6Hz), 7.07-7.35(3H,m), 7.37(1H,d,J=8.0 Hz), 7.67(1H,d,J=7.8 Hz),8.17(1H,bs).

(5S)-2-[N-(2-ethylhexyloxycarbonyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3298, 1769, 1742. ¹H-NMR (CDCl₃) δ: 0.90(6H,t,J=7.6 Hz),1.26-1.60(9H,m), 3.29(3H,s), 3.90(1H,m), 4.19(2H,d,J=5.8 Hz),5.12(1H,d,J=3.0 Hz), 7.06-7.38(4H,m), 7.66(1H,d,J=7.6 Hz), 8.14(1H,bs).

(5S)-2-[N-(4-acetoxybenzyloxycarbonyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3333, 1746. ¹H-NMR (CDCl₃) δ: 1.24(3H,d,J=7.4 Hz),2.41(3H,s), 3.50(3H,s), 3.80(1H,m), 5.09(1H,d,J=2.8 Hz), 5.30(2H,s),6.52(1H,d,J=2.2 Hz), 7.03-7.46(7H,m), 7.57(1H,d,J=7.6 Hz), 8.56(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(4-nitrobenzyloxycarbonyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3299, 1773, 1746. ¹H-NMR (CDCl₃) δ: 1.44(3H,d,J=7.2 Hz),3.35(3H,s), 3.90(1H,m), 5.15(1H,d,J=2.6 Hz), 5.37(2H,s),7.03-7.24(3H,m), 7.37(1H,d,J=8.2 Hz), 7.47(2H,d,J=8.8 Hz),7.64(1H,d,J=8.4 Hz), 8.10(1H,bs), 8.14(2H,d,J=8.8 Hz).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-phenoxycarbonyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3281, 1779, 1746. ¹H-NMR (CDCl₃) δ: 1.45(3H,d,J=7.2 Hz),3.47(3H,s), 3.91(1H,m), 5.15(1H,d,J=3.0 Hz), 7.03-7.49(9H,m),7.67(1H,d,J=7.4 Hz), 8.05(1H,bs).

Example 4

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(N-(4-methoxyphenyl)carbamoyl)-N-methyl]amino-2-oxazolin-4-one

To a mixture of indolmycin (150 mg) and dichloromethane (3 ml) was added4-methoxyphenylisocyanate (261 mg) under ice cooling. After the mixturewas sitrred for 2 hours at room temperature, the solvent was distilledoff to give a residue. After isopropylether was added to the residue,the titled compound was obtained as a crystal (213 mg, 89.9%).

IR (KBr) cm⁻¹: 3382, 1717. ¹H-NMR (CDCl₃) δ: 1.48(3H,d,J=7.0 Hz),3.34(3H,s), 3.78(3H,s), 3.95(1H,m), 5.08(1H,d,J=3.0 Hz), 6.83(2H,d,J=9.2Hz), 7.11-7.40(6H,m), 7.67(1H,d,J=8.4 Hz), 8.21(1H,bs), 11.21(1H,bs).

Example 5

Following the same procedure as described in the Example 4, thefollowing compounds were prepared.

(5S)-2-[N-(N-(4-chlorophenyl)carbamoyl)-N-methyl]amino-5-[(1R)-2-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3372, 1713. ¹H-NMR (CDCl₃) δ: 1.49(3H,d,J=7.4 Hz),3.34(3H,s), 3.97(1H,m), 5.09(1H,d,J=3.2 Hz), 7.15-7.47(8H,m),7.67(1H,d,J=7.4 Hz), 8.17(1H,bs), 11.48(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(N-(2-phenylethyl)carbamoyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3243, 1713. ¹H-NMR (CDCl₃) δ: 1.44(3H,d,J=7.4 Hz),2.82(2H,t,J=8.0 Hz), 3.28(3H,s), 3.47(2H,m), 3.91(1H,m), 5.02(1H,d,J=3.0Hz), 7.11-7.40(9H,m), 7.65(1H,d,J=7.8 Hz), 8.15(1H,bs), 9.33(1H,bs).

(5S)-2-[N-(N-(2,4-dimethoxyphenyl)carbamoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3397, 1711. ¹H-NMR (CDCl₃) δ: 1.45(3H,d,J=7.2 Hz),3.37(3H,s), 3.79(3H,s), 3.89(3H,s), 3.92(1H,m), 5.07(1H,d,J=2.8 Hz),6.42-6.47(2H,m), 7.14-7.26(3H,m), 7.39(1H,d,J=7.4 Hz), 7.69(1H,d,J=6.8Hz), 7.90(1H,d,J=9.2 Hz), 8.14(1H,bs), 11.45(1H,bs).

(5S)-2-[N-(N-(7-ethoxycarbonylheptyl)carbamoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3235, 1716. ¹H-NMR (CDCl₃) δ: 1.17-1.32(9H,m),1.45(3H,d,J=7.4 Hz), 1.50-1.72(4H,m), 2.30(2H,t,J=7.4 Hz), 3.20(2H,m),3.28(3H,s), 4.13(2H,q,J=7.0 Hz), 5.02(1H,d,J=3.0 Hz), 7.10-7.25(3H,m),7.38(1H,d,J=7.6 Hz), 7.65(1H,d,J=7.8 Hz), 8.34(1H,bs), 9.18(1H,bs).

Example 6

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-(4-trifluromethylbenzoyl)-N-methyl]amino-2-oxazolin-4-one

To a well stirred mixture of indolmycin (150 mg), triethylamine (325 μl), 4-dimethylaminopyridine (39.8 mg), and tetrahydrofuran (10 ml) underthe ice cooling, 4-trifluoromethylbenzoylchloride (260 μl) was added.The mixture was stirred for 30 minutes at 0° C. and ethyl acetate wasadded. The whole was washed with water, saturated aqueous sodiumhydrogen carbonate solution and brine respectively and then the ethylacetate solution was dried over MgSO₄. Removal of the organic solventgave a residue, which was subjected to silica-gel chromatography.Elution with hexane-acetone (4:1) provided the titled compound (176 mg,70.4%). m.p. 146-148° C.

IR (KBr) cm⁻¹: 3390, 1749, 1714. ¹H-NMR (CDCl₃) δ: 1.42(3H,d,J=7.2 Hz),3.41(3H,s), 3.77-3.89(1H,m), 4.92(1H,d,J=2.8 Hz), 6.64(1H,d,J=2.0 Hz),7.13-7.56(8H,m), 8.03(1H,bs).

Example 7

Following the same procedure as described in the Example 6, thefollowing compounds were prepared.

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-(2-trifluoromethylbenzoyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3287, 1748, 1717. ¹H-NMR (CDCl₃) δ: 1.23(3H,d,J=7.2 Hz),3.51(3H,s), 3.68(1H,m), 4.87(1H,d,J=2.8 Hz), 6.60(1H,d,J=1.8 Hz),7.08-7.26(3H,m), 7.36-7.61(5H,m), 8.02(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(3-trifluoromethylbenzoyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3335, 1715. ¹H-NMR (CDCl₃) δ: 1.37(3H,d,J=7.2 Hz),3.41(3H,s), 3.78(1H,m), 4.91(1H,d,J=3.4 Hz), 6.62(1H,d,J=2.2 Hz),7.11-7.40(5H,m), 7.51(1H,d,J=8.0 Hz), 7.73(1H,d,J=7.4 Hz), 7.78(1H,s),8.00(1H,bs).

(5S)-2-[N-(4-fluorobenzoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3300, 1741, 1707. ¹H-NMR (CDCl₃) δ: 1.44(3H,d,J=7.4 Hz),3.38(3H,s), 3.76-3.90(1H,m), 4.93(1H,d,J=3.0 Hz), 6.76(1H,d,J=2.4 Hz),6.92-7.00(2H,m), 7.09-7.27(4H,m), 7.40(1H,d,J=8.0 Hz), 7.56(1H,d,J=7.2Hz), 8.13(1H,bs).

(5S)-2-[N-(4-chlorobenzoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3296, 1746, 1705. ¹H-NMR (CDCl₃) δ: 1.42(3H,d,J=7.4 Hz),3.38(3H,s), 3.75-3.86(1H,m), 4.93(1H,d,J=3.0 Hz), 6.70(1H,d,J=2.6 Hz),7.09-7.28(6H,m), 7.40(1H,d,J=7.8 Hz), 7.55(1H,d,J=8.0 Hz), 8.09(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(4-methylbenzoyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3300, 1744, 1703. ¹H-NMR (CDCl₃) δ: 1.36(3H,d,J=7.4 Hz),2.39(3H,s), 3.38(3H,s), 3.71-3.83(1H,m), 4.89(1H,d,J=3.0 Hz),6.59(1H,d,J=2.2 Hz), 7.06-7.38(7H,m), 7.50(1H,d,J=8.4 Hz), 8.00(1H,bs).

(5s)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(4-methoxybenzoyl)-N-methyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3299, 1744, 1701. ¹H-NMR (CDCl₃) δ: 1.39(3H,d,J=7.4 Hz),3.38(3H,s), 3.82(3H,s), 4.91(1H,d,J=2.8 Hz), 6.67(1H,d,J=2.2 Hz),6.81(2H,d,J=8.8 Hz), 7.06-7.26(3H,m), 7.36(2H,d,J=8.8 Hz),7.52(1H,d,J=7.4 Hz), 8.01(1H,bs).

(5S)-2-(N-cinnamoyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3395, 1753, 1682, 1615. ¹H-NMR (CDCl₃) δ: 1.46(3H,d,J=7.2Hz), 3.38(3H,s), 3.88-3.99(1H,m), 5.14(1H,d,J=3.0 Hz), 7.06-7.82(12H,m),7.96(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-nicotinoyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3277, 1748, 1703. ¹H-NMR (CDCl₃) δ: 1.48(3H,d,J=7.4 Hz),3.37(3H,s), 3.79-3.92(1H,m), 4.95(1H,d,J=3.4 Hz), 6.80(1H,d,J=2.2 Hz),7.09-7.58(6H,m), 8.12(1H,d,J=2.2 Hz), 8.40(1H,bs), 8.63(1H,dd,J=1.8&4.8Hz).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-phenylacetyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3300, 1724. ¹H-NMR (CDCl₃) δ: 1.45(3H,d,J=7.0 Hz),3.25(3H,s), 3.85-3.99(1H,m), 4.10(1H,d,J=16.6 Hz), 4.25(1H,d,J=16.6 Hz),5.05(1H,d,J=2.8 Hz), 6.98-7.39(9H,m), 7.63(1H,d,J=8.6 Hz), 8.18(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-(2-thiophene)carbonyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3289, 1739, 1672. ¹H-NMR (CDCl₃) δ: 1.48(3H,d,J=7.4 Hz),3.37(3H,s), 3.81-3.90(1H,m), 4.99(1H,d,J=3.0 Hz), 6.87-7.66(8H,m),8.08(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-(2-thienyl)acetyl]amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3298, 1726. ¹H-NMR (CDCl₃) δ: 1.49(3H,d,J=7.2 Hz),3.26(3H,s), 3.88-3.99(1H,m), 4.34(1H,d,J=17.6 Hz), 4.51(1H,d,J=17.6 Hz),5.09(1H,d,J=3.2 Hz), 6.80-7.22(6H,m), 7.38(1H,d,J=7.4 Hz),7.64(1H,d,J=7.6 Hz), 8.17(1H,bs).

(5S)-2-(N-heptanoyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3275, 1732. ¹H-NMR (CDCl₃) δ: 0.88(3H,t,J=6.2 Hz),1.18-1.33(6H,m), 1.47(3H,d,J=7.2 Hz), 1.55-1.63(2H,m), 2.84(2H,q,J=5.4Hz), 3.26(3H,s), 3.87-3.99(1H,m), 5.07(1H,d,J=3.0 Hz), 7.09-7.25(3H,m),7.38(1H,d,J=7.4 Hz), 7.65(1H,d,J=7.4 Hz), 8.14(1H,bs).

(5S)-2-(N-heptanoyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3320, 1717. ¹H-NMR (CDCl₃) δ: 1.11-1.39(6H,m),1.50(3H,d,J=7.2 Hz), 1.53-1.83(4H,m), 3.23(3H,s), 3.46-3.60(1H,m),3.85-3.99(1H,m), 5.06(1H,d,J=3.0 Hz), 7.09-7.24(3H,m), 7.37(1H,d,J=7.0Hz), 7.65(1H,d,J=7.6 Hz), 8.11(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-pivaloyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3287, 1736, 1624. ¹H-NMR (CDCl₃) δ: 1.12(9H,s),1.47(3H,d,J=7.4 Hz), 3.16(3H,s), 3.90(1H,m), 5.02(1H,d,J=3.0 Hz),7.08-7.26(3H,m), 7.36(1H,d,J=7.2 Hz), 7.64(1H,d,J=7.2 Hz), 8.27(1H,bs).

(5S)-2-(N-heptanoyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3378, 1750, 1722. ¹H-NMR (CDCl₃) δ: 1.47(3H,d,J=7.0 Hz),2.48(3H,s), 3.25(3H,s), 3.94(1H,m), 5.08(1H,d,J=3.4 Hz),7.09-7.22(3H,m), 7.38(1H,d,J=7.4 Hz), 7.65(1H,d,J=8.0 Hz), 8.15(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-isobutyl-N-methyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3300, 1736, 1725. ¹H-NMR (CDCl₃) δ: 0.86(3H,d,J=7.0 Hz),1.07(3H,d,J=6.8 Hz), 1.50(3H,d,J=7.4 Hz), 3.24(3H,s), 3.86(1H,m),3.94(1H,m), 5.05(1H,d,J=3.0 Hz), 7.09-7.23(3H,m), 7.36(1H,d,J=7.4 Hz),7.64(1H,d,J=7.4 Hz), 8.13(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-propionyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3381, 1736, 1723. ¹H-NMR (CDCl₃) δ: 1.05(3H,t,J=7.2 Hz),1.47(3H,d,J=7.2 Hz), 2.87(2H,m), 3.26(3H,s), 3.88-4.00(1H,m),5.06(1H,d,J=3.0 Hz), 7.09-7.25(3H,m), 7.38(1H,d,J=7.4 Hz),7.64(1H,d,J=7.4 Hz), 8.13(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-palmitoyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3370, 1726. ¹H-NMR (CDCl₃) δ: 0.88(3H,t,J=6.6 Hz),1.16-1.19(26H,m), 1.46(3H,d,J=7.2 Hz), 2.82(2H,m), 3.25(3H,s),3.91(1H,m), 5.06(1H,d,J=3.2 Hz), 7.09-7.21(3H,m), 7.37(1H,d,J=7.4 Hz),7.64(1H,d,J=7.8 Hz), 8.12(1H,bs).

Example 8

(5S)-2-[N-(2-benzyloxybenzoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

To a well stirred mixture of indolmycin (400 mg), triethylamine (868 μl)and 4-dimethylaminopyridine (106 mg) in tetrahydrofuran (20 ml) wasadded 2-benzyloxybenzoylchloride (1.15 g) under the ice cooling. Themixture was stirred for 40 minutes at 0° C. and ethyl acetate was added.The whole was washed with water, saturated aqueous sodium hydrogencarbonate solution and brine respectively and then the ethyl acetatesolution was dried over MgSO₄. Removal of the organic solvent gave aresidue, which was subjected to silica-gel chromatography. Elution withhexane-acetone (5:1) provided the titled compound (534 mg, 73.3%).

IR (KBr) cm⁻¹: 3303, 1744, 1701. ¹H-NMR (CDCl₃) δ: 1.15(3H,d,J=7.0 Hz),3.40(3H,s), 3.65(1H,m), 4.68(1H,d,J=2.6 Hz), 4.97(2H,s), 6.28(1H,d,J=2.6Hz), 6.89(1H,d,J=8.4 Hz), 7.04-7.50(12H,m), 7.85(1H,bs).

Example 9

(5S)-2-[N-(2-hydroxybenzoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

To a solution of

(5S)-2-[N-(2-benzyloxybenzoyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one(420 mg) in tetrahydrofuran (10 ml) was added 10% palladium-carbon (300mg). The whole was subjected to hydrogenation and then filtered toremove the catalyst. The filtrate was distilled off to give a residue,which was treated with ether to provide the titled compound (104 mg,30.7%) as a crystal.

IR (KBr) cm⁻¹: 3430, 3250, 1752, 1649. ¹H-NMR (DMSO-d₆) δ:1.38(3H,d,J=7.4 Hz), 2.59(3H,s), 3.56(1H,m), 4.77(1H,d,J=3.0 Hz),6.89-7.84(9H,m), 10.62(1H,bs), 10.87(1H,bs).

Example 10

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-(1-piperidinocarbonyl)-N-methyl]amino-2-oxazolin-4-one

To a mixture of indolmycin (150 mg) and triethylamine (324 μl) intetrahydrofuran (7.0 ml) was added 4-nitrophenyl chloroformate (353 mg)at 0° C. The mixture was stirred for 15 minutes at 0° C. and thenpiperidine (173 μl) was added. After the whole was further stirred for 8minutes at 0° C., ethyl acetate was added. The whole was washed withwater, saturated aqueous sodium hydrogen carbonate solution and brinerespectively and then the ethyl acetate solution was dried over MgSO₄.Removal of the organic solvent gave a residue, which was subjected tosilica-gel chromatography. Elution with hexane-acetone (3:1) providedthe titled compound (154 mg, 71.6%).

IR (KBr) cm⁻¹: 3279, 1698. ¹H-NMR (CDCl₃) δ: 1.20-1.75(9H,m),3.09-3.35(5H,m), 3.40-3.70(2H,m), 3.88(1H,m), 4.99(1H,d,J=2.6 Hz),7.10-7.19(3H,m), 7.34(1H,d,J=7.4 Hz), 7.67(1H,d,J=8.4 Hz), 8.17(1H,bs).

Example 11

(5S)-2-[N-(N-benzyloxycarbonyl-L-alanyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

To a mixture of N-benzyloxycarbonyl-L-alanine (893 mg) and triethylamine(1.11 ml) in tetrahydrofuran (10 ml) was added ethyl chloroformate (381μl) at −15° C. The mixture was stirred for 5 minutes at −15° C. and thenindolmycin (257 mg) was added. After the whole was further stirred for 8minutes at 0° C., ethyl acetate was added. The whole was warmed up toroom temperature and stirred for 40 minutes. Ethyl acetate was added tothe mixture. The mixture was washed with water, saturated aqueous sodiumhydrogen carbonate solution and brine respectively and then the ethylacetate solution was dried over MgSO₄. Removal of the organic solventgave a residue, which was subjected to silica-gel chromatography.Elution with hexane-acetone (4:1) provided the titled compound (387 mg,83.3%).

IR (KBr) cm⁻¹: 3233, 1715. ¹H-NMR (CDCl₃) δ: 1.26-1.60(6H,m),2.20(3H,s), 4.14(1H,m), 5.05-5.24(4H,m), 6.69(1H,s), 7.11-7.36(9H,m),7.64(1H,bs), 8.11(1H,s).

Example 12

Following the same procedure as described in the Example 11, thefollowing compounds were prepared.

(5S)-2-[N-(N-benzyloxycarbonylglycyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3277, 1717. ¹H-NMR (CDCl₃) δ: 1.55(3H,d,J=7.8 Hz),2.44(3H,s), 3.91(1H,d,J=15.8 Hz), 4.01(1H,d,J=15.8 Hz), 4.53(1H,m),5.11(2H,s), 5.20(1H,m), 6.61(1H,s), 7.15-7.34(9H,m), 7.62(1H,m),8.13(1H,bs).

(5S)-2-[N-(N-benzyloxycarbonyl-L-leucyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3300, 1717. ¹H-NMR (CDCl₃) δ: 0.75(6H,m),1.44-1.81(6H,m), 2.19(3H,s), 4.14(1H,m), 5.01-5.27(4H,m), 6.67(1H,s),7.07-7.22(4H,m), 7.33(5H,m), 7.60(1H,m), 8.11(1H,bs).

(5S)-2-[N-(N-benzyloxycarbonyl-L-phenylalanyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3375, 1719. ¹H-NMR (CDCl₃) δ: 1.31(1H,d,J=7.4 Hz),1.45(2H,d,J=7.2 Hz), 3.13(3H,s), 3.50(2H,m), 4.42(1H,m), 4.52(1H,m),5.08-5.44(3H,m), 6.70-7.60(15H,m), 8.04(1H,s).

(5S)-2-[N-(N-benzyloxycarbonyl-L-prolyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3324, 1701. ¹H-NMR (CDCl₃) δ: 1.28(1.5H,d,J=7.2 Hz),1.42(1.5H,d,J=5.2 Hz), 1.90(3H,m), 2.39(1H,m), 3.11(1.5H,s),3.30(1.5H,s), 3.51-3.66(2H,m), 3.89(1H,m), 4.89-5.21(3H,m),5.40-5.52(1H,m), 7.01-7.36(9H,m), 8.01(0.5H,bs), 8.19(0.5H,bs).

(5S)-2-[N-(N-benzyloxycarbonyl-L-γ-benzylglutaminyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3354, 1719. ¹H-NMR (CDCl₃) δ: 1.56(3H,m), 1.75(2H,m),2.17(3H,s), 2.40(2H,m), 3.73(1H,m), 4.25(1H,m), 5.00-5.22(5H,m),7.11-7.34(14H,m), 7.64(1H,m), 8.10(1H,bs)

Example 13

(5S)-2-[N-(N-(L-alanyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

To a solution of

(5S)-2-[N-(N-benzyloxycarbonyl-L-alanyl)-N-methyl]amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one(387 mg) in tetrahydrofuran (4 ml) was added 10% palladium-carbon (100mg). The whole was subjected to hydrogenation and then filtered toremove the catalyst. The filtrate was distilled off to give a residue,which was treated with ether to provide the titled compound (141 mg,51.6%) as a crystal.

IR (KBr) cm⁻¹: 3372, 3287, 1736, 1633. ¹H-NMR (CDCl₃) δ: 1.26(3H,d,J=7.0Hz), 1.52(3H,d,J=7.0 Hz), 3.13(3H,s), 3.80(1H,m), 4.22(1H,q,J=7.0 Hz),4.53(1H,bs), 7.07-7.22(2H,m), 7.36(1H,d,J=7.2 Hz), 7.72(1H,d,J=7.0 Hz),8.02(1H,bs), 9.09(1H,bs).

Example 14

Following the same procedure as described in Example 13, the followingcompounds were prepared.

(5S)-2-(N-glycyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3333, 1748, 1630. ¹H-NMR (CDCl₃) δ: 1.27(3H,d,J=7.2 Hz),3.14(3H,s), 3.80(1H,m), 4.15(2H,s), 4.54(1H,d,J=2.8 Hz),7.08-7.22(2H,m), 7.36(1H,d,J=7.2 Hz), 7.72(1H,d,J=7.4 Hz), 8.03(1H,bs),9.02(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-L-leucyl-N-methyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3368, 1759, 1644. ¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=4.8 Hz),1.27(3H,d,J=7.0 Hz), 1.63(1H,m), 1.77(2H,m), 3.13(3H,s), 3.80(1H,m),4.18(1H,dd,J=3.8&9.2 Hz), 4.52(1H,d,J=2.6 Hz), 7.07-7.21(2H,m),7.36(1H,d,J=7.4 Hz), 7.72(1H,d,J=7.4 Hz), 8.02(1H,bs), 9.18(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-L-phenylalanyl-N-methyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3380, 1707, 1637. ¹H-NMR (CDCl₃) δ: 1.22(3H,d,J=7.0 Hz),2.93(1H,dd,J=14.0&8.4 Hz), 3.04(3H,s), 3.32(1H,d,J=14.0&4.0 Hz),3.95(1H,m), 4.37(1H,dd,J=8.4&4.0 Hz), 7.07-7.41(9H,m), 7.70(1H,d,J=8.0Hz), 8.01(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-L-prolyl-N-methyl)amino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3289, 1707. ¹H-NMR (CDCl₃) δ: 1.51(3H,d,J=7.4 Hz),1.89(2H,m), 2.06(2H,m), 2.78(3H,s), 3.00(1H,m), 3.25(1H,m), 3.80(2H,m),4.83(1H,d,J=3.2 Hz), 6.59(1H,s), 7.09-7.21(3H,m), 7.38(1H,d,J=7.4 Hz),7.64(1H,d,J=7.8 Hz), 8.13(1H,bs).

(5S)-2-(N-L-glutaminyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3299, 1724, 1623. ¹H-NMR (DMSO-d₆) δ: 1.18(3H,d,J=6.8Hz), 2.03(2H,m), 2.22(2H,m), 2.99(3H,s), 3.66(1H,m), 4.27(2H,m),6.91-7.12(3H,m), 7.32(1H,d,J=7.4 Hz), 7.58(1H,d,J=6.6 Hz), 9.57(1H,bs).

Example 15

(5S)-5-[(1R)-1-(indol-3-yl)ethyl-2-(N-methanesulfonyl-N-methyl)amino-2-oxazolin-4-one

To a mixture of indolmycin (100 mg) and triethylamine (217 μl) intetrahydrofuran (5 ml) was added methanesulfonylchloride (90.3 μl) at−30° C. The whole was stirred for 5 minutes at −30° C. and then furtherstirred at 0° C. for 1 hour. Ethyl acetate was added to the mixture. Themixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and brine respectively and then the ethyl acetatesolution was dried over MgSO₄. Removal of the organic solvent gave aresidue, to which was added isopropylether to provide the titledcompound (74 mg, 57.0%).

IR (KBr) cm⁻¹: 3303, 1748. ¹H-NMR (CDCl₃) δ: 1.53(3H,d,J=7.4 Hz),2.88(3H,s), 3.33(3H,s), 3.88-3.97(1H,m), 5.06(1H,d,J=3.4 Hz),7.10-7.25(3H,m), 7.37(1H,d,J=7.0 Hz), 7.67(1H,d,J=7.8 Hz), 8.28(1H,bs).

Example 16

Following the same procedure as described in Example 15, the followingcompounds were prepared.

(5S)-2-(N-benzenesulfonyl-N-methyl)amino-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one

IR (KBr) cm⁻¹: 3300, 1748. ¹H-NMR (CDCl₃) δ: 1.23(3H,d,J=7.2 Hz),3.54(3H,s), 3.76-3.89(1H,m), 4.99(1H,d,J=2.6 Hz), 7.15-7.78(10H,m),8.12(1H,bs).

Example 17

5-[1-(6-fluoroindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one

To a solution of acetoaldehyde (1.0 g) in toluene (7 ml) was addedisopropylamine (1.3 g). The mixture was dried over magnesium sulfate andfiltered. The filtrate was added to a solution of 6-fluoroindole (3.32g) in acetic acid (20 ml) under ice cooling. The whole was stored atfreezer for 3 days and was poured into the ice water. The mixture wasneutralized with 25% ammonia water. The whole was extracted with ethylacetate. The extract was washed with brine and then dried over MgSO₄.Removal of the solvent gave a residue, to which a mixture of ethylacetate and ethyl ether was added to provide6-fluoro-3-(1-isopropylamino)ethylindole (1.31 g) as a crystal. ¹H-NMR(CDCl₃) δ: 1.07(6H,m), 1.49(3H,d,J=6.6 Hz), 2.85(1H,m), 4.23(1H,q,6.6Hz), 6.80-7.10(3H,m), 7.62(1H,dd,J=5.4&8.4 Hz), 8.12(1H,bs).

To a mixture of 6-fluoro-3-(1-isopropylamino)ethylindole (435 mg),benzyl 2-dimethylamino-4-oxo-2-oxazolin-5-carboxylate (518 mg) inacetonitrile (15 ml) was added tri-n-butylphosphine (492 μl). Themixture was refluxed for 2.5 hours. Removal of the solvent gave aresidue, to which a mixture of ethyl acetate and ethyl ether in a rationof 10:1 was added to provide benzyl2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate(509 mg) as a crystal.

¹H-NMR (CDCl₃) δ: 1.28(2H,d,J=7.2 Hz), 1.51(1H,d,J=7.2 Hz),2.84-3.26(6H,m), 4.24(1H,m), 4.99(1.4H,ABq,J=4.8 Hz),5.32(0.7H,ABq,J=4.8 Hz), 6.70-7.70(9H,m), 8.14(0.7H,bs), 8.45(0.35H,bs).

Benzyl2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate(500 mg) was dissolved into 15 ml of a solution of ethanol andtetrahydrofuran in a ration of 5:1. 10% palladium-carbon (170 mg) wasadded. The whole was subjected to hydrogenation under normal temperatureand normal pressure for 1.5 hours. The whole was stirred at 80° C. undernitrogen atmosphere for 1 hour and then filtered to remove the catalyst.The filtrate was concentrated to give2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-2-oxazolin-4-one (340mg).

¹H-NMR (CDCl₃) δ: 1.43(1.2H,d,J=7.2 Hz), 1.62(1.8H,d,J=7.2 Hz),2.97-3.06(6H,m), 3.60-3.80(1H,m), 4.90(0.6H,d,J=1.5 Hz),4.97(0.4H,d,J=1.5 Hz), 6.85(1H,m), 6.90-7.30(2H,m), 7.58(1H,m),8.66(0.4H,bs), 8.67(0.6H,bs).

2-Dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-2-oxazolin-4-one (340mg) was dissolved into methylamine (5 ml) at −10° C. The mixture wasstirred for 3 hours at the same temperature. The mixture wasconcentrated to give a residue, which was subjected to columnchromatography. Elution with hexane-acetone (1:1) provided the titledcompound (254 mg).

IR (KBr) cm⁻¹: 3195, 1733, 1644, 1627. ¹H-NMR (DMSO-d₆) δ:1.18(0.9H,d,J=7.2 Hz), 1.27(0.4H,d,J=7.4 Hz), 1.43(1.1H,d,J=7.2 Hz),1.49(0.6H,d,J=7.2 Hz), 2.60-2.80(3H,m), 3.40-3.60(1H,m),4.80-5.00(1H,m), 6.81(1H,m), 7.00-7.20(2H,m), 7.55(1H,m),8.50-8.70(1H,bs), 10.9-11.0(1H,m).

Example 18

Following the same procedure as described in Example 11, the followingcompounds were prepared.

(5S)-2-[N-(3-benzyloxycarbonylaminopropionyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3327, 2971, 1715, 1557, 1539, 1456, 1397, 1316, 1246,1200, 1138. ¹H-NMR (CDCl₃) δ: 1.48(3H,d,J=7.4 Hz), 2.76-3.07(2H,m),3.20(3H,s), 3.30-3.42(2H,m), 3.93(1H,m), 5.06(1H,d,J=3.2 Hz),5.11(2H,s), 7.07-7.22(3H,m), 7.30-7.40(6H,m), 7.62(1H,d,J=7.8 Hz),8.24(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-[3-(N-benzyloxycarbonyl-N-methyl)amino]propionyl-N-methylamino]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3296, 1700-1750, 1646. ¹H-NMR (CDCl₃) δ: 1.38-1.50(3H,m),2.86(1.2H,s), 2.90(1.8H,s), 2.97-3.11(2H,m), 3.16(1.8H,s), 3.22(1.2H,s),3.4-3.6(2H,m), 3.92(1H,m), 5.04(1H,d,J=2.8 Hz), 5.13(2H,s),6.9-7.4(9H,m), 7.61(1H,d,J=7.4 Hz), 8.1-8.3(1H,bs).

(5S)-2-[N-(4-benzyloxycarbonylaminobutyryl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3337, 2969, 2940, 1711, 1561, 1537, 1454, 1433, 1397,1314, 1252, 1192. ¹H-NMR (CDCl₃) δ: 1.48(3H,d,J=7.4 Hz), 1.64(2H,m),2.76(2H,m), 3.12(2H,m), 3.23(3H,s), 3.93(1H,m), 4.82(1H,bs),5.05(1H,d,J=3.2 Hz), 5.12(2H,s), 7.00-7.41(9H,m), 7.62(1H,d,J=6.8 Hz),8.35(1H,bs).

(5S)-2-[N-(4-benzylsuccinyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3400, 1733, 1558, 1538, 1456, 1432, 1394, 1209, 1166.¹H-NMR (CDCl₃) δ: 1.46(3H,d,J=7.3 Hz), 2.52-2.66(2H,m), 2.99-3.34(2H,m),3.24(3H,s), 3.93(1H,dq,J=7.3&3.0 Hz), 5.06(1H,d,J=3.0 Hz), 5.12(2H,s),7.07-7.38(9H,m), 7.63(1H,d,J=7.2 Hz), 8.10(1H,bs).

(5S)-2-[N-[(2S)-2,5-bis(N-benzyloxycarbonylamino)-pentanoyl]-N-methylamino-5-[(1R)-1-(indol-3-yl)ethyl-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3327, 3064, 3033, 2968, 2939, 2877, 1718, 1523, 1455,1388, 1345, 1263, 1220. ¹H-NMR (CDCl₃) δ: 1.25-1.55(4H,m), 1.57(3H,d,J=6Hz), 2.33(3H,s), 2.70-2.90(2H,m), 4.15-4.30(2H,m), 4.83-5.29(7H,m),7.07-7.68(15H,m), 8.12(1H,bs).

(5S)-2-[N-[(S)-4-benzyl(N-benzylcarbonylamino)-aspartyl]-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3396, 3064, 3035, 2970, 2937, 1722, 1455, 1423, 1386,1344, 1311. ¹H-NMR (CDCl₃) δ: 1.36,1.60(total 3H,d,J=7.8 Hz),2.19(3H,s), 2.28-3.18(2H,m), 3.78(1H,m), 4.21(1H,m), 4.29-4.47(1H,m),4.99-5.32(5H,m), 6.70-7.47(14H,m), 7.68(1H,d,J=8.2 Hz), 8.10(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-[(S)-4-methyl[N-benzyloxycarbonylamino)-aspartyl]-N-methylamino]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3402, 3060, 3037, 2954, 2937, 1722, 1457, 1436, 1376,1344, 1313. ¹H-NMR (CDCl₃) δ: 1.36,1.61(total 3H,d,J=7.6 Hz),2.20(3H,s), 2.82-3.82(3H,m), 3.57,3.60(total 3H,s), 4.18-4.50(2H,m),5.02-5.32(3H,m), 6.85-7.36(9H,m), 7.45,7.68(total 1H,d,J=7.2 Hz),8.14(1H,bs).

(5S)-2-[N-(2-tert-butyldimethylsilyloxyoctanoyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

¹H-NMR (CDCl₃) δ: -0.1-0.1(6H,m), 0.85(4.5H,s), 0.87(4.5H,s),1.0-1.2(10H,m), 1.46(3H,t,J=7.0 Hz), 3.25(1.5H,s), 3.26(1.5H,s),3.93(1H,dq,J=3.0&7.0 Hz), 5.05(0.5H,d,J=3.0 Hz), 5.07(0.5H,d,J=3.0 Hz),5.40-5.48(1H,m), 7.1-7.7(5H,m), 8.13(1H,bs).

(5S)-2-[N-(2-benzyloxyoctanoyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 1810, 1733, 1704, 1634. ¹H-NMR (CDCl₃) δ: 0.8-0.9(3H,m),1.1-1.4(9H,m), 1.45(3H,d,J=7.2 Hz), 1.5-1.83(1H,m), 3.2-3.3(3H,m),3.89(1H,dq,J=3.0&7.2 Hz), 3.97-4.73(3H,m), 5.03(0.5H,m),5.11-5.17(0.5H,m), 6.9-7.7(10H,m), 8.11(0.5H,bs), 8.16(0.5H,bs).

(5S)-2-(N-benzyloxyacetyl-N-methylamino)-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3347, 1733, 1627, 1557. ¹H-NMR (CDCl₃) δ: 1.46(3H,d,J=7.2Hz), 3.26(3H,s), 3.92(1H,dq,J=3.4&7.2 Hz), 4.42,4.66(2H,ABq,J=18.0 Hz),4.55(2H,s), 5.05(1H,d,J=3.4 Hz), 7.0-7.7(10H,m), 8.09(1H,bs).

(5S)-2-[N-(2-benzyloxy-4-methylpentanoyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 1742, 1729, 1557, 1538. ¹H-NMR (CDCl₃) δ: 0.66,0.78(each3H,d,J=6.6 Hz), 0.88,0.93(3H,d,J=7.0 Hz), 1.3-1.6(3H,m), 3.2-3.3(3H,m),3.91(1H,m), 3.8-4.6(2.5H,m), 5.00-5.05(1H,m), 5.25(0.5H,m),7.0-7.7(10H,m), 8.09-8.2(1H,m).

Example 19

Following the same procedure as described in Example 6, the followingcompounds were prepared.

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-lauroyl-N-methylamino]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3298, 2925, 2854, 1729, 1558, 1538, 1455, 1394, 1195.¹H-NMR (CDCl₃) δ: 0.83(3H,t,J=6.6 Hz), 1.23-1.35(16H,m), 1.46(3H,d,J=7.2Hz), 1.51-1.64(2H,m), 2.85(2H,m), 3.25(3H,s), 3.93(1H,m),5.06(1H,d,J=3.0 Hz), 7.09-7.25(3H,m), 7.37(1H,d,J=7.8 Hz),7.64(1H,d,J=7.8 Hz), 8.14(1H,bs).

(5S)-2-[N-chloroacetyl-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3383, 2972, 1733, 1558, 1455, 1436, 1398, 1340, 1317,1203. ¹H-NMR (CDCl₃) δ: 1.52(3H,d,J=7.3 Hz), 3.28(3H,s), 3.95(1H,m),4.48(1H,d,J=16.5 Hz), 4.72(1H,d,J=16.5 Hz), 5.08(1H,d,J=3.3 Hz),7.08-7.26(3H,m), 7.38(1H,d,J=7.4 Hz), 7.62(1H,d,J=7.6 Hz), 8.25(1H,bs).

(5S)-2-[N-[2-(5-amino-1,2,4-thiodiazol-3-yl)-2(Z)-ethoxyiminoacetyl]-N-methylamino]-5-(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3400, 2976, 1747, 1714, 1616, 1538, 1455, 1403, 1245,1224. ¹H-NMR (CDCl₃) δ: 1.14(3H,t,J=7.1 Hz), 1.23(3H,m), 3.56(3H,s),3.79(1H,m), 5.08(1H,m), 6.85-7.25(5H,m), 7.33(1H,d,J=8.2 Hz),7.56(1H,d,J=7.0 Hz), 8.60(1H,bs).

(5S)-2-(N-allyloxalyl-N-methylamino)-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 1746, 1704, 1634, 1615. ¹H-NMR (CDCl₃) δ:1.25-1.45(3H,m), 3.00-3.11(3H,m), 3.76(1H,dq,J=3.4&7.2 Hz),4.90-5.01(3H,m), 5.40(1H,d,J=11.2 Hz), 5.51(1H,dd,J=1.2&17.0 Hz),5.95-6.15(1H,m), 7.1-7.7(5H,m), 8.46(1H,bs).

Example 20

Following the same procedure as described in Example 13, the followingcompounds were prepared.

(5S)-2-[N-(3-aminopropionyl)-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3266, 2969, 2928, 1705, 1622, 1584, 1495, 1456, 1399,1341, 1308, 1236. ¹H-NMR (CDCl₃) δ: 1.27(3H,d,J=7.0 Hz), 2.78(2H,t,J=7.0Hz), 3.30(3H,s), 3.56(2H,t,J=7.0 Hz), 3.65(2H,bs), 3.77(1H,m),4.48(1H,m), 7.06-7.21(3H,m), 7.35(1H,d,J=7.6 Hz), 7.71(1H,d,J=7.0 Hz),8.08(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-[(S)-4-methylaspartyl]-N-methylamino]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3352, 2966, 1735, 1643, 1577, 1488, 1457, 1438, 1403,1322, 1255, 1099. ¹H-NMR (CDCl₃) δ: 1.27(3H,d,J=7.1 Hz),2.73(1H,dd,J=17.6&9.0 Hz), 3.07(1H,dd,J=17.6&3.4 Hz), 3.15(3H,s),3.57(1H,bs), 3.76(3H,s), 3.82(1H,m), 4.46(1H,dd,J=9.0&3.4 Hz),4.54(1H,m), 7.03-7.27(3H,m), 7.36(1H,d,J=7.0 Hz), 7.73(1H,d,J=7.4 Hz),8.07(1H,bs), 9.12(1H,bs).

(5S)-2-[N-[(S)-aspartyl]-N-methylamino]-5-[(1R)-1-(indol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3400, 1720, 1629, 1560, 1425, 1399, 1342. ¹H-NMR(DMSO-d₆) δ: 1.17(3H,d,J=7.0 Hz), 2.30-2.70(2H,m), 2.99(3H,s),3.64(1H,m), 4.24-4.38(2H,m), 6.93-7.36(4H,m), 7.60(1H,d,J=8.0 Hz),10.78(1H,bs).

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-[N-methyl-N-(3-methylaminopropionyl)amino]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3244, 1733, 1607. ¹H-NMR (CDCl₃) δ: 1.49(2.0H,d,J=7.4Hz), 1.54(1.0H,d,J=7.4 Hz), 1.9-2.5(2H,m), 2.59(1.0H,d,J=2.4 Hz),2.71(2.0H,d,J=2.4 Hz), 2.97(2.0H,s), 3.00(1.0H,s), 3.4-3.6(1H,m),3.6-3.8(1H,m), 3.86(1H,dq,J=3.0&7.4 Hz), 4.80(0.33H,bs), 4.98(1H,d,J=3.0Hz), 6.08(0.67H,bs), 7.0-7.7(5H,m), 8.64(0.67H,bs), 8.70(0.33H,bs).

Example 21

(5S)-2-[N-(2-benzylphthaloyl)-N-methylamino]-5-[(1R)-1-(indoly-3-yl)ethyl]-2-oxazolin-4-one

To a solution of mono-benzyl phthalic ester (1.60 g) in toluene (20 ml)was added thionyl chloride (1 ml). After being stirred for one hour at80° C., the mixiture was concentrated under the reduced pressure toafford a residue. Tetrahydrofuran (20 ml) was added to the residue andthen indolmycin (400 mg) was added at −15° C. After triethylamine (1.74ml) was added, the mixture was stirred for 21 hours at room temperature.The whole was diluted with ethyl acetate (100 ml). The mixture waswashed with water (35 ml), saturated aqueous sodium hydrogen carbonatesolution (35 ml×3) and brine (35 ml) respectively and the dried overMgSO₄. Concentration of the solution under the reduced pressure gave aresidue, which was subjected to column-chromatography. Eluent with ethylacetate-hexane was collected and concentrated. The content wassolidified from hexane. The solid product was collected by filtrationand dried to provide the titled compound (161 mg).

IR (KBr) cm⁻¹: 3400, 1714, 1538, 1455, 1399, 1278, 1222. ¹H-NMR (CDCl₃)δ: 1.07(3H,d,J=7.1 Hz), 3.44(3H,s), 3.60(1H,m), 4.72(1H,d,J=2.6 Hz),5.17(1H,d,J=12.0 Hz), 5.26(1H,d,J=12.0 Hz), 6.31(1H,d,J=2.4 Hz),7.06-7.52(12H,m), 7.86(1H,bs), 7.95(1H,dd,J=7.6&1.4 Hz).

Example 22

(5S)-5-[(1R)-1-(indol-3-yl)ethyl]-2-(N-methyl-N-trifluoroacetylamino)-2-oxazolin-4-one

Indolmycin (401 mg) was dissolved into tetrahydrofuran (38 ml). To thissolution were added triethylamine (1.5 ml) and trifluoroacetic anhydride(1.0 ml). The whole was stirred for 1 hour at room temperature. Themixture was diluted with ethyl acetate (100 ml). The whole was washedwith water, brine and dried over magnesium sulfate. The solution wasconcentrated to give a residue, which was subjected to silica gelchromatography. Elution with hexane-acetone (1:1) gave the titledcompound (375 mg).

IR (KBr) cm⁻¹: 1733, 1652, 1634, 1615. ¹H-NMR (CDCl₃) δ:1.33(0.45H,d,J=7.0 Hz), 1.34(2.55H,d,J=7.0 Hz), 2.97-3.13(3H,m),3.77(1H,dq,J=2.2&7.0 Hz), 4.85(0.15H,d,J=2.2 Hz), 4.97(0.85H,d,J=2.2Hz), 7.3-7.7(5H,m), 8.4-8.51(1H,bs).

Example 23

2-methylamino-5-[(5-chloroindol-3-yl)methyl]-2-oxazolin-4-one

To a solution of 5-chloro-3-formylindole (5.00 g) in tetrahydrofuran(135 ml) was added sodium hydride (60% oil suspension, 3.53 g). Themixture was stirred for 20 minutes at room temperature.Carbobenzoxychloride (6.64 ml) was added to the mixture. After beingstirred for 1 hour at room temperature, the whole was poured into icewater. The mixture was extracted with ethyl acetate. The extract waswashed with brine and dried over magnesium sulfate. The solution wasconcentrated to give a residue, which was subjected to silica gelchromatography. Elution with hexane-ethyl acetate (5:1) provided1-benzyloxycarbonyl-5-chloro-3-formylindol (5.74 g) as a crystal.

¹H-NMR (CDCl₃) δ: 5.51(2H,s), 7.36-7.52(6H,m), 8.10(1H,d,J=9.2 Hz),8.27(1H,s), 8.30(1H,d,J=2.2 Hz), 10.06(1H,s).

To a solution of 1-benzyloxycarbonyl-5-chloro-3-formylindol (2.00 g) inmethanol (13 ml) was added sodium borohydride (241 mg) at 0° C. Afterthe mixture was stirred for 15 minutes at the same temperature, icewater was added to the mixture. Potassium carbonate was added to makethe mixture saturate. The whole was extracted with ether and the extractwas dried over magnesium sulfate. Concentration of the mixture gave aresidue, to which hexane was added.1-benzyloxycarbonyl-5-chloro-3-hydroxymethylindol (1.80 g) was obtainedas a crystal.

¹H-NMR (CDCl₃) δ: 1.63(1H,t,J=5.0 Hz), 4.79(2H,d,J=5.0 Hz), 5.44(2H,s),7.26-7.45(6H,m), 7.63(2H,s), 8.09(1H,d,J=8.8 Hz).

To a solution of 1-benzyloxycarbonyl-5-chloro-3-hydroxymethylindole(1.45 g) in dichloromethane (23 ml) was added thionylchloride (0.797 μl)at −78° C. After the mixture was stirred for 1.5 hours at roomtemperature, the reaction mixture was concentrated under the reducedpressure to give a residue. Hexane was added to the residue.1-benzyloxycarbonyl-5-chloro-3-chloromethylindole (1.43 g) was obtainedas a crystal.

¹H-NMR (CDCl₃) δ: 4.70(2H,s), 5.44(2H,s), 7.32(1H,dd,J=8.8&1.8 Hz),7.39-7.46(5H,m), 7.64(1H,d,J=1.8 Hz), 7.69(1H,s), 8.10(1H,d,J=8.8 Hz).

To a solution of diisopropylamine (1.18 ml) in tetrahydrofuran (24 ml)was added a 1.6 M solution (5.24 ml) of n-butyllithium in hexane underice cooling. The mixture was cooled to −78° C., to which was added2-dimethylamino-2-oxazolin-4-one (1.07 g). The mixture was stirred for30 minutes at room temperature and cooled again to −78° C.1-benzyloxycarbonyl-5-chloro-3-chloromethylindol (1.40 g) was added. Thewhole was stirred at −78° C. to −40° C. for 30 minutes, at 0° C. for 2hours and at room temperature for 40 minutes respectively. To thereaction mixture was added water and the whole was extracted with ethylacetate. The extract was dried over magnesium sulfate and concentratedto give a residue, which was subjected to silica gel chromatography.Elution with hexane-ethyl acetate (1:1) gave5-[(5-chloroindol-3-yl)methyl-2-dimethylamino-2-oxazolin-4-one (232 mg)as a crystal.

¹H-NMR (CDCl₃) δ: 2.96(3H,s), 2.98(3H,s), 3.22(1H,dd,J=15.8&4.0 Hz),3.45(1H,dd,J=15.8&4.0 Hz), 4.98(1H,t,J=4.0 Hz), 7.07(1H,s),7.09(1H,d,J=8.8 Hz), 7.29(1H,d,J=8.8 Hz), 7.59(1H,s), 8.64(1H,bs).

To [(5-chloroindol-3-yl)methyl]-2-dimethylamino-2-oxazolin-4-one (200mg) was added methylamine (20 ml). The mixture was refluxed at −6° C.for 1 hour. Removal of methylamine gave a residue, to which was addedether. The titled compound (120 mg) was obtained as a crystal.

IR (KBr) cm⁻¹: 2986, 1641, 1413, 1390, 1304, 1242, 1103. ¹H-NMR(DMSO-d₆) δ: 2.73(3H,s), 3.01(1H,m), 3.19(1H,m), 4.95(1H,m),7.03(1H,d,J=8.8 Hz), 7.20(1H,s), 7.34(1H,dd,J=8.8&1.8 Hz),7.58(1H,d,J=1.8 Hz), 8.31(1H,bs).

Example 24

Following the same procedure as described in Example 23, the followingcompounds were prepared.

2-methylamino-5-[(2-methylindol-3-yl)methyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 2912, 1655, 1508, 1408, 1305, 1251, 1238, 746. ¹H-NMR(DMSO-d₆) δ: 2.50(3H,s), 2.70(3H,s), 2.93-3.20(2H,m), 4.86(1H,m),6.86-7.00(2H,m), 7.20(1H,d,J=7.2 Hz), 7.40(1H,d,J=6.9 Hz),8.48(1H,bs),10.76(1H,bs).

5-[(5-benzyloxyindol-3-yl)methyl]-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 1667, 1640, 1485, 1412, 1304. ¹H-NMR (DMSO-d₆) δ:2.68(1.5H,s), 2.99(1H,m), 3.21(1H,m), 4.95(1H,dd,J=7.0&3.4 Hz),6.79(1H,d,J=8.8 Hz), 7.08-7.52(8H,m), 10.78(1H,bs).

2-methylamino-5-[(5,6-methylenedioxyindoly-3-yl)methyl]-2-oxazolin-4-one,

¹H-NMR (DMSO-d₆) δ: 2.73(3H,d,J=5.0 Hz), 2.96-3.15(2H,m),4.89-4.91(1H,m), 5.92(2H,s), 6.85(1H,s), 6.96(1H,s), 6.99(1H,s),8.58(1H,bs).

Example 25

2-methylamino-5-(1H-pyrro[2,3-b]pyridin-3-yl)methyl-2-oxazolin-4-one

To a solution of diisopropylamine (0.75 ml) in tetrahydrofuran (35 ml)was added 1.6M solution (3.35 ml) of n-butyllithium in hexane under icecooling. The whole was cooled to −78° C.2-dimethylamino-2-oxazolin-4-one (686 mg) was added and then the wholewas stirred for 30 minutes at room temperature. The mixture was cooledagain to −78° C., to which was added3-chloromethyl-1H-pyrro[2,3-b]pyridine (230 mg). The whole was stirredfor 4 hours at room temperature. To the reaction mixture was added waterand the whole was extracted with ethyl acetate. The extract was driedover magnesium sulfate and concentrated to give a residue, which wassubjected to silica gel chromatography. Elution with ethylacetate-ethanol (10:1) provided2-dimethylamino-5-(1H-pyrro[2,3-b]pyridin-3-yl)methyl-2-oxazolin-4-one(51 mg).

1H-NMR (CDCl₃) δ: 2.95(3H,s), 3.03(3H,s), 3.26(1H,dd,J=15.9&5.5 Hz),3.48(1H,dd,J=15.9&4.3 Hz), 4.97(1H,dd,J=5.5&4.3 Hz),7.09(1H,dd,J=7.9&4.8 Hz), 7.24(1H,s), 7.98(1H,dd,J=7.9&1.5 Hz),8.29(1H,J=4.8&1.5 Hz), 9.64(1H,bs).

2-dimethylamino-5-(1H-pyrro[2,3-b]pyridin-3-yl)methyl-2-oxazolin-4-one(50 mg) was added to methylamine (1 ml). After the reaction mixture wasrefluxed for 1 hour, methylamine was removed to give a residue, whichwas subjected to silica gel chromatography. Eluent with ethylacetate-ethanol was concentrated to give a residue, which was solidifiedusing chloroform. The solid was washed with diethyl ether and driedunder the reduced pressure to give the titled compound (32 mg).

IR (KBr) cm⁻¹: 3215, 1645, 1516. ¹H-NMR (DMSO-d₆) δ: 2.71,2.73(total3H,each s), 2.99-3.32(2H,m), 4.97(1H,dd,J=6.7&3.9 Hz),7.03(1H,dd,J=7.8&4.7 Hz), 7.24(1H,d,J=2.1 Hz), 7.96(1H,d,J=7.8 Hz),8.18(1H,d,J=4.7 Hz), 8.58(1H,bs), 11.43(1H,bs).

Example 26

Following the same procedure as described in Example 25, the followingcompounds were prepared.

5-(bezo[b]thiophen-3-yl)methyl-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3210, 1768, 1678. 1H-NMR (DMSO-d₆) δ: 2.68,2.79(total3H,each s), 3.18(1H,dd,J=15.7&8.4 Hz), 3.42(1H,m), 5.06(1H,m),7.35-7.45(2H,m), 7.51(1H,s), 7.82-7.99(2H,m), 8.69(1H,bs).

5-[(1-benzylindol-3-yl)methyl]-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 1663, 1508, 1410, 1402, 1298, 729. ¹H-NMR (DMSO-d₆) δ:2.68(1H,s), 2.72(2H,s), 3.07(1H,m), 3.30(1H,m), 4.98(1H,dd,J=6.2&2.4Hz), 5.37(2H,s), 6.96-7.38(9H,m), 7.56(1H,d,J=7.0 Hz), 8.55(1H,bs).

Example 27

Following the same procedure as described in Example 17, the followingcompounds were prepared.

5-[(1-(4-methylindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3183, 1733, 1623. ¹H-NMR (CDCl₃) δ: 1.25-1.50(3H,m),2.69-3.0(3H,m), 4.05-4.25(1H,m), 4.86(0.5H,d,J=3.6 Hz),4.96(0.5H,d,J=2.6 Hz), 6.84(1H,m), 6.98-7.25(3H,m), 8.29(0.5H,bs),8.38(0.5H,bs), 9.30(1H,bs).

5-[(1-(4-benzyloxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3199, 1733, 1652, 1615. ¹H-NMR (CDCl₃) δ:1.22-1.37(3H,m), 2.82-3.0(3H,m), 4.1-4.4(1H,m), 5.08(0.5H,d,J=4.8 Hz),5.19(1.5H,m), 5.26(1H,s), 6.56(1H,m), 6.9-7.1(3H,m), 7.29-7.6(5H,m),8.23(0.5H,bs), 8.37(0.5H,bs), 9.25(1H,bs).

2-methylamino-5-[1-(7-methylindol-3-yl)ethyl]-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3357, 3214, 1733, 1652, 1615. ¹H-NMR (DMSO-d6) δ:1.18(0.96H,d,J=7.4 Hz), 1.25(0.45H,d,J=7.0 Hz), 1.42(0.96H,d,J=7.2 Hz),1.50(0.63H,d,J=7.6 Hz), 2.41(1.5H,s), 2.44(1.5H,s), 2.65-2.8(3H,m),3.5-3.7(1H,m), 4.8-4.95(1H,m), 6.8-6.9(2H,m), 7.0-7.15(1H,m),7.35-7.45(1H,m), 8.55(1H,bs).

5-[1-(4-methoxycarbonylindoly-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one,

IR (KBr) cm⁻¹: 3278, 3203, 1713, 1635. ¹H-NMR (DMSO-d₆) δ:1.06(1.33H,d,J=7.0 Hz), 1.14(0.67H,d,J=7.0 Hz), 1.32(0.67H,d,J=7.0 Hz),1.41(0.33H,d,J=7.6 Hz), 2.7-2.85(3H,m), 3.86(1.08H,s), 3.91(1.92H,s),3.95-4.2(1H,m), 4.65-4.85(1H,m), 7.0-7.2(1H,m), 7.3-7.5(2H,m),7.55-7.65(1H,m), 11.40(1H,bs).

5-[1-(4-isopropylindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one.

IR (KBr) cm⁻¹: 3266, 3216, 1725, 1634. ¹H-NMR (DMSO-d₆) δ:1.1-1.5(9H,m), 2.75-2.9(3H,m), 3.6-3.9(1H,m), 4.8-4.95(1H,m),6.8-7.1(2H,m), 7.1-7.25(2H,m), 8.67(1H,bs).

Example 28

5-[1-(4-hydroxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one

5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one (149mg) was dissolved in a mixture of ethanol and tetrahydrofuran (5:1.6ml). 10% palladium-carbon (45 mg) was added and the whole washydrogenated for 24 hours at room temperature under normal pressure. Thecatalyst was removed from the mixture by filtration and 10%palladium-carbon (45 mg) was added again. The whole was hydrogenated foradditional 24 hours at room temperature under normal pressure. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated to give a residue, which was subjected to silica gelchromatography. Elution with hexane-acetone (1:1) provided the titledcompound (72 mg).

IR (KBr) cm⁻¹: 3189, 1733, 1698, 1615. ¹H-NMR (DMSO-d₆) δ:1.0-1.15(1.92H,m), 1.30-1.35(1.08H,m), 2.7-2.85(3H,m), 3.7-4.0(1H,m),4.92(0.12H,d,J=6.0 Hz), 5.02(0.31H,d,J=6.0 Hz), 5.08(0.20H,d,J=2.2 Hz),5.13(0.37H,d,J=2.2 Hz), 6.32(1H,d,J=5.2 Hz), 6.7-7.0(3H,m), 8.58(1H,bs),9.40(1H,bs).

Example 29

5-[1-(4-methoxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one

5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-dimethylamino-2-oxazolin-4-one (268mg) was dissolved in a mixture of ethanol and tetrahydrofuran (7:3.10ml). 10% palladium-carbon (80 mg) was added and the whole washydrogenated for 5 hours at room temperature under normal pressure. Thecatalyst was removed from the mixture and 10% palladium-carbon (80 mg)was added again. The whole was hydrogenated for additional 24 hours atroom temperature under normal pressure. The reaction mixture wasfiltered to remove the catalyst. The filtrate was concentrated to give2-dimethylamino-5-[1-(4-hydroxyindol-3-yl)ethyl]-2-oxazolin-4-one (125mg).

¹H-NMR (DMSO-d₆) δ: 1.02-1.15(3H,m), 3.00-3.10(6H,m), 3.98(1H,m),4.97-5.16(1H,m), 6.30-6.34(1H,m), 6.77-6.83(2H,m), 6.95(1H,m),9.40(1H,bs), 10.69(1H,bs).

2-dimethylamino-5-[1-(4-hydroxyindol-3-yl)ethyl]-2-oxazolin-4-one (120mg) was dissolved into dimethylformamide (3 ml). Potassium carbonate(115 mg) and indomethane (156 μl) were added. The mixture was stirredfor 3 hours at room temperature and additional indomethane (78 μl) wasadded. The mixture was stirred for 36 hours at room temperature. To thereaction mixture was added water and the whole was extracted with ethylacetate. The extract was washed with brine and dried over magnesiumsulfate. Concentration of the ethyl acetate solution gave a residue,which was subjected to silica gel chromatography. Elution withhexane-acetone (1:1) provided2-dimethylamino-5-[1-(4-methoxyindol-3-yl)ethyl-2-oxazolin-4-one (54mg).

¹H-NMR (CDCl₃) δ: 1.26(2.6H,d,J=7.0 Hz), 1.45(0.4H,d,J=7.2 Hz),2.96(0.4H,s), 3.00(2.6H,s), 3.17(2.6H,s), 3.19(0.4H,s), 3.90(0.4H,s),3.93(2.6H,s), 4.25(1H,m), 4.98(0.13H,d,J=3.4 Hz), 5.24(0.87H,d,J=2.2Hz), 6.51(d,J=7.8 Hz), 6.95-7.14(3H,m), 8.16(1H,bs).

2-dimethylamino-5-[1-(4-methoxyindol-3-yl)ethyl]-2-oxazolin-4-one (50mg) was added to methylamine (5 ml). The mixture was refluxed for 5hours and additional methylamine (5 ml) was added. The whole was furtherrefluxed for 2.5 hours. The-methylamine was distilled off to give aresidue, which was subjected to silica gel chromatography. Elution withhexane-acetone (1:1) provided the titled compound (32 mg).

IR (KBr) cm⁻¹: 3286, 3199, 1733, 1623. ¹H-NMR (DMSO-d₆) δ:1.0-1.15(3H,m), 2.7-2.85(3H,m), 3.84(3H,s), 3.7-3.9(1H,m),4.98(0.33H,d,J=2.2 Hz), 5.01(0.67H,d,J=2.2 Hz), 6.46(1H,m),6.9-7.1(3H,m), 8.60(1H,bs), 10.88(1H,bs).

Example 30

5-[1-(4-chloroindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one

3-chloroindole (500 mg) and ethyl trans-2,3-epoxybutyrate (472 mg) weredissolved into dichloromethane (5 ml). To this mixture was added at −9°C. over 30 minutes titanium tetrachloride. The whole was stirred for 1hour at −9° C. Ethyl trans-2,3-epoxybutyrate (405 mg) and titaniumtetrachloride (405 μl) were added. The whole was further stirred for 1hour at −9° C. Concentration of the reaction mixture gave a residue, towhich was added ethyl acetate. The mixture was washed with brine anddried over magnesium sulfate. Concentration of the solution gave aresidue, which was subjected to silica gel chromatography. Elution withhexane-ethyl acetate (1:3) provided ethyl(2S*,3R*)-3-(4-chloroindol-3-yl)-2-hydroxybutylate (200 mg).

¹H-NMR (CDCl₃) δ: 1.27(3H,d,J=7.2 Hz), 1.33(3H,t,J=7.0 Hz),2.81(1H,d,J=5.2 Hz), 4.25-4.40(4H,m), 4.64(1H,dd,J=5.2&2.6 Hz),7.06-7.10(2H,m), 7.24-7.29(2H,m), 8.22(1H,bs).

Sodium (100 mg) was dissolved into ethanol (5 ml). Ethyl(2S*,3R*)-3-(4-chloroindol-3-yl)-2-hydroxybutyrate (200 mg) andN,N′-dimethyl guanidine hydrogen bromide (143 mg) were added. The wholewas refluxed for 16 hours. To the reaction mixture was added water andextracted with ethyl acetate. The extract was washed with brine anddried over magnesium sulfate. Concentration of the solution gave aresidue, which was subjected to silica gel chromatography. Elution withhexane-acetone (1:1) provided the titled compound (25 mg).

¹H-NMR (CDCl₃) δ: 1.27-1.44(3H,m), 2.84-3.00(3H,m), 4.36-4.58(1H,m),4.99-5.11(1H,m), 5.88(1H,m), 7.00-7.30(4H,m), 8.60-8.80(1H,m).

Example 31

5-[1-(indol-3-yl)-2,2,2-trifluoroethyl]-2-methylamino-2-oxazolin-4-one

Sodium ethoxide (580 mg) was added to a solution of methyl4,4,4-trifluoro-2-hydroxy-3-(indol-3-yl)butyrate (980 mg) andN,N′-dimethyl guanidine hydrogen bromide (630 mg) in ethanol (2.5 ml).The mixture was refluxed for 1.5 hours and then cooled. To the cooledreaction mixture was added ice water (20 ml). After the pH of themixture was adjusted to 7 using acetic acid, the whole was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogen carbonate solution and then dried over magnesium sulfate.Concentration of the solution under the reduced pressure gave residue,which was subjected to silica gel chromatography. Eluent with ethylacetate-hexane was collected and concentrated to provide the titledcompound (218 mg).

IR (KBr) cm⁻¹: 3283, 1769, 1717, 1659, 1541. ¹H-NMR (DMSO-d₆) δ:2.38-2.54(3H,m), 3.65-4.61(2H,m), 6.24-6.33(1H,m), 6.94-7.98(5H,m),11.10-11.18(1H,m).

Example 32

2-diacetylamino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one

2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (300 mg) was dissolvedinto tetrahydrofuran (2 ml). Triethylamine (344 μl) and acetyl chloride(123 μl) were added under ice cooling. The mixture was stirred for 2hours at 0° C. Triethylamine (344 μl) and acetyl chloride (123 μl) wereadded again. The whole was further stirred for 2 hours. To the reactionmixture was added water and the whole was extracted with ethyl acetate.The extract was washed with brine and dried over magnesium sulfate.Concentration of the solution gave a residue, which was subjected tosilica gel chromatography. The eluent with hexane-acetone (1:1) wascollected and concentrated to provide the titled compound (40 mg).

1H-NMR (CDCl₃) δ: 1.45(1.92H,d,J=7.2 Hz), 1.57(1.08H,d,J=7.2 Hz),2.17(6H,s), 3.7-3.9(1H,m), 4.99(0.36H,d,J=2.4 Hz), 5.07(0.64H,d,J=2.8Hz), 7.0-7.4(4H,m), 7.6-7.7(1H,m), 8.32(1H,bs).

Example 33

2-acetylamino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one

2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (100 mg) was dissolvedinto pyridine (0.5 ml). Acetic anhydride (117 μl) was added. The mixturewas stirred for 2 hours at 80° C. To the reaction mixture was addedwater. The mixture was made acidic using 4N hydrochloric acid. The wholewas extracted with ethyl acetate. The extract was washed with brine anddried over magnesium sulfate. Concentration of the solution gave aresidue, which was subjected to the silica gel chromatography. Theeluent with hexane-acetone (1:1) was collected and concentrated toprovide the titled compound (16 mg).

IR (KBr) cm⁻¹: 1742, 1698. ¹H-NMR (CDCl₃) δ: 1.42(1.95H,d,J=7.2 Hz),1.62(1.05H,d,J=7.2 Hz), 2.1-2.3(3H,m), 3.88(1H,dq,J=2.2&7.2 Hz),5.00(0.35H,d,J=2.2 Hz), 5.04(0.65H,d,J=2.2 Hz), 7.0-7.4(5H,m),7.67(1H,d,J=8.4 Hz), 8.19(1H,bs).

Experimental Example 1

In vitro antimicrobial test:

Determination of invitro antimicrobial activity against Helicobacterpylori and other microorganisms

Using 5 strains of Helicobacter pylori, 19 other bacterial species and 2yeast species as test strains, the antimicrobial activities of variouscompounds were determined by the method described below (agar dilutionmethod). The test compound was dissolved in dimethyl sulfoxide; thissolution was 2-fold diluted step by step with sterilized distilled waterto yield test samples. Two milliliters of each test sample was mixedwith 18 ml of Brucella agar supplemented with 7% horse blood as a mediumto prepare a determination plate. Helicobacter pylori was subjected toshaking culture at 37° C. in a gas pack jar incorporating CampyPak™(BBL^(R) Beckton Dickinson Microbiology Systems) for 20 hours, usingBrucella broth medium supplemented with 2.5% fetal bovine serum, toyield a seed inoculum. The other test microorganisms were each culturedat 37° C. for 20 hours, using Brucella broth medium, to yield respectiveseed inocula.

Five microliters of each seed inoculum, previously adjusted to about 10⁶CFU/ml using Brucella broth medium supplemented with 2.5% fetal bovineserum was inoculated to each determination plate, and cultured at 37° C.in a gas pack jar incorporating CampyPak™ and water-soaked cottonabsorbent for 4 days. After cultivation, strain growth wasmacroscopically examined; the minimum concentration for the absence ofstrain growth was taken as the MIC value (minimum inhibitoryconcentration) of the test compound.

The results are shown in Tables 2 and 3.

TABLE 2 Antimicrobial Activities of Indolmycin against VariousMicroorganisms [MIC (μg/ml)] 1 Escherichia coli K12 >100 2 Escherichiacoli NIHJ JC-2 >100 3 Proteus mirabilis ATCC 21100 >100 4 Proteusvulgaris IFO 3045 >100 5 Proteus morganii IFO 3168 >100 6 Klebsiellapneumoniae IFO 3317 >100 7 Serratia marcescens IFO 3046 >100 8Salmonella typhimurium IFO 12529 >100 9 Salmonella enteritidis IFO3313 >100 10 Citrobater freundii IFO 12681 >100 11 Pseudomonasaeruginosa IFO 3080 >100 12 Alcaligenes faecalis IFO 13111 >100 13Bacillus subtilis PCI 219 >100 14 Bacillus cereus IFO 3514 >100 15Bacillus pumilus IFO 3813 >100 16 Bacillus megaterium IFO 12108 >100 17Staphylococcus aureus FDA 209P >100 18 Micrococcus luteus IFO 12708 12.519 Micrococcus flavus IFO 3242 >100 20 Helicobacter pylori NCTC 116370.006 21 Candida albicans IFO 0583 >100 22 Saccharomyces cerevisiae IFO0209 >100

TABLE 3 Antimicrobial Activities against Various Strains of Helicobacterpylori (in vitro) MIC (μg/ml) H. pylori H. H. H. pylori H. pylori CPYpylori pylori Compound NCTC 11637 NCTC 11916 433 TN 2 TN 58 Indolmycin0.006 0.013 0.013 0.006 0.025 Compound of 0.025 — 0.05 0.025 0.05Example 2 MIC was determined by agar dilution method using Brucella agarsupplemented with 7% horse blood.

As seen from Tables 2 and 3, compound (I) exhibits very selectiveantimicrobial activity against the bacteria of the genus Helicobacter,represented by Helicobacter pylori.

Experimental Example 2

(In vivo antimicrobial activity test)

After mongolian gerbils (MGS/Sea, male, 6 weeks of age) were fasted for24 hours, Helicobacter pylori TN2GF4 was inoculated to the stomach at10^(7.08) per mongolian gerbil. Starting at 11 days after infection, a3, 10, 30, or 100 mg/kg suspension of the test compound in a 0.5%aqueous solution of methyl cellulose was orally administered twice daily(morning and evening) for 3 days. On the day after final administration,the stomach of each infected mongolian gerbil was excised and disrupted;a series of 10-fold dilutions of the stomach homogenate were eachinoculated to modified Skirrow's medium supplemented with activatedcharcoal and cultured under microaerophilic conditions at 37° C. for 4days, after which clearance effect was assessed on the basis of thepresence or absence of bacterial growth. The results are shown in Table4. Bacterial cell counts are expressed in mean±standard deviation afterDunnett's test against the control group. In Table 4, ** indicatesp<0.01.

TABLE 4 Bacterial Detection Dose Clearance (log CFU/ Test Compound(mg/kg) Rate (%) gastric wall) Control (0.5% methyl — 0/4 (0) 6.36 ±0.19 cellulose solution) Indolmycin  3 0/5 (0) 4.61 ± 1.84  10 0/5 (0)2.76 ± 1.04**  30 1/4 (25) 1.96 ± 0.78** 100 4/5 (80) 1.48 ± 0.00**

As shown in Table 4, indolmycin at 10 mg/kg or higher reduced themongolian gerbil gastric bacterial cell count with dose dependency, theclearance rates achieved being 25% at 30 mg/kg and 80% at 100 mg/kg.

These findings demonstrate that the preparation of the present inventionis effective against the gastric ulcer, gastritis and gastric cancercaused by Helicobacter pylori infection.

Preparation Example

For use as a therapeutic agent for Helicobacter pylori infections, thepreparation of the present invention, which contains a compoundrepresented by formula (I) or a salt thereof, can be produced with thefollowing formulations:

1. Capsules (1) Indolmycin 100 mg (2) Lactose 90 mg (3) Microcrystallinecellulose 70 mg (4) Magnesium stearate 10 mg Total 270 mg per capsule

Components (1), (2) and (3) and a half portion of component (4) weremixed and granulated. To these granules, the remaining portion ofcomponent (4) was added, and the whole mixture was packed in a gelatincapsule.

2. Tablets (1) Indolmycin 100 mg (2) Lactose 35 mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mgTotal 320 mg per tablet

Components (1), (2) and (3), a two-third portion of component (4) and ahalf portion of component (5) were mixed and granulated. To thesegranules, the remaining portions of components (4) and (5) were added,and the whole mixture was tableted by compressive tableting.

Industrial Applicability

Compound (I) or a salt thereof exhibits very specific potentantibacterial activity against the bacteria of the genus Helicobacterrepresented by Helicobacter pylori. The use of compound (I) of thepresent invention or a salt thereof therefore provides the desiredeffect for an anti-Helicobacter pylori agent at doses much lower thanthe effective doses of conventional antibacterial agents for thebacteria of the genus Helicobacter (especially Helicobacter pylori).

Compound (I) or a salt thereof is effective in the prevention ortreatment of various diseases caused by bacteria of the genusHelicobacter such as duodenal ulcer, gastric ulcer, chronic gastritisand gastric cancer, and, because Helicobacter pylori is a major cause ofulcer recurrence, compound (I) or a salt thereof is also effective inthe prevention of ulcer recurrence.

Also, compound (I) or a salt thereof exhibits no antibacterial actionagainst gram-positive bacteria such as those of the generaStaphylococcus and Bacillus and against gram-negative bacteria such asthose of the genera Escherichia, Pseudomonas, Proteus, Klebsiella,Serratia, Salmonella, Citrobacter and Alcaligenes. Compound (I) or asalt thereof is therefore selectively effective in the prevention ortreatment of diseases caused by bacteria of the genus Helicobacter, andcan be used as a safe pharmaceutical without adverse effects havinglittle influence on other bacteria and fungi.

Compound (I) or a salt thereof is stable and of low toxicity.Accordingly, the present invention provides an excellentanti-Helicobacter pylori agent without adverse effects.

What is claimed is:
 1. A compound of the formula:

wherein: A is an indolyl group which is unsubstituted or substituted by(1) a hydroxyl group, (2) a halogen atom, (3) a nitro group, (4) a cyanogroup, (5) a C₁₋₄ alkyl group which is unsubstituted or substituted by 1to 5 halogens, (6) a C₁₋₄ alkoxy group which is unsubstituted orsubstituted by 1 to 5 halogens, (7) a benzyloxy group, (8) a C₁₋₄ alkoxycarbonyl group, (9) a methylene dioxo or (10) ethylene dioxo; R¹ and R²are independently (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alknyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₄₋₆ cycloalkadienyl group,or (8) an aryl group {wherein each of the above (2), (3), (4), (5), (6),(7) and (8) is unsubstituted or substituted by 1 to 5 substituentsselected from the group consisting of {circle around (1)} an aryl groupwhich is unsubstituted or substituted by 1 to 2 substituents selectedfrom the group consisting of an alkoxy group having 1 to 3 carbon atoms,a halogen atom, and an alkyl group having 1 to 3 carbon atoms, {circlearound (2)} a C₃₋₇ cycloalkyl or C₃₋₆ cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} an amino group which is unsubstituted or substitutedby an alkyl group having 1 to 3 carbon atoms, {circle around (4)} ahydroxyl group which is unsubstituted or substituted by an alkyl grouphaving 1 to 3 carbon atoms, {circle around (5)} a thiol group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, and {circle around (6)} a halogen; and wherein each of the above(5), (6), (7) and (8) is unsubstituted or substituted by 1 to 5 C₁₋₃alkyls}, R^(3′) is (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₃₋₆ cycloalkadienyl, (8) anaryl group {wherein each of the above (2), (3), (4), (5), (6), (7) and(8) is unsubstituted or substituted by {circle around (1)} an aryl groupwhich is unsubstituted or substituted by an alkoxy group having 1 to 3carbon atoms, a halogen atom, or an alkyl group having 1 to 3 carbonatoms, {circle around (2)} a cycloalkyl or cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} a hydroxyl group which is unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, {circle around(4)} a thiol group which is unsubstituted or substituted by an alkylgroup having 1 to 3 carbon atoms, or {circle around (5)} a halogen; andwherein each of the above (5), (6), (7) and (8) is unsubstituted orsubstituted by C₁₋₃ alkyl}; and R^(4′″) is (24) a carboxyl group, (25) aC₂₋₈ alkoxycarbonyl group, (26) a C₇₋₁₂ aryloxycarbonyl group, or (27) aC₈₋₁₀ aralkyloxycarbonyl group {wherein each of the above (26) and (27)is unsubstituted or substituted by a hydroxyl group, an amino groupwhich may substituted by 1 or 2 substituents selected from the groupconsisting of a C₁₋₄ alkyl, formyl, acetyl, propionyl and benzoyl, ahalogen, a nitro, a cyano, a C₁₋₄ alkyl which is unsubstituted orsubstituted by 1 to 5 halogens, or C₁₋₄ alkoxy which is unsubstituted orsubstituted by 1 to 5 halogens}, or a salt thereof.
 2. A compound as inclaim 1, wherein: A is indolyl; R¹ and R² independently represent ahydrogen atom or methyl; R³ is methyl; and R⁴ is an esterified carboxylgroup.
 3. A composition, comprising (i) a compound of the formula:

wherein: A is an indolyl group which is unsubstituted or substituted by(1) a hydroxyl group, (2) a halogen atom, (3) a nitro group, (4) a cyanogroup, (5) a C₁₋₄ alkyl group which is unsubstituted or substituted by 1to 5 halogens, (6) a C₁₋₄ alkoxy group which is unsubstituted orsubstituted by 1 to 5 halogens, (7) a benzyloxy group, (8) a C₁₋₄ alkoxycarbonyl group, (9) a methylene dioxo or (10) ethylene dioxo; R¹ and R²are independently (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₄₋₆ cycloalkadienyl group,or (8) an aryl group {wherein each of the above (2), (3), (4), (5), (6),(7) and (8) is unsubstituted or substituted by 1 to 5 substituentsselected from the group consisting of {circle around (1)} an aryl groupwhich is unsubstituted or substituted by 1 to 2 substituents selectedfrom the group consisting of an alkoxy group having 1 to 3 carbon atoms,a halogen atom, and an alkyl group having 1 to 3 carbon atoms, {circlearound (2)} a C₃₋₇ cycloalkyl or C₃₋₆ cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} an amino group which is unsubstituted or substitutedby an alkyl group having 1 to 3 carbon atoms, {circle around (4)} ahydroxyl group which is unsubstituted or substituted by an alkyl grouphaving 1 to 3 carbon atoms, {circle around (5)} a thiol group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, and {circle around (6)} a halogen; and wherein each of the above(5), (6), (7) and (8) is unsubstituted or substituted by 1 to 5 C₁₋₃alkyls}; and R^(3′) and R^(4′) are independently (1) a hydrogen atom,(2) a C₁₋₇ alkyl group, (3) a C₂₋₆ alkenyl group, (4) a C₂₋₆ alkynylgroup, (5) a C₃₋₉ cycloalkyl group, (6) a C₃₋₆ cycloalkenyl group, (7) aC₃₋₆ cycloalkadienyl, (8) an aryl group {wherein each of the above (2),(3), (4), (5), (6), (7) and (8) is unsubstituted or substituted by{circle around (1)} an aryl group which is unsubstituted or substitutedby an alkoxy group having 1 to 3 carbon atoms, a halogen atom, or analkyl group having 1 to 3 carbon atoms, {circle around (2)} a cycloalkylor cycloalkenyl group which is unsubstituted or substituted by an alkoxygroup having 1 to 3 carbon atoms, a halogen atom, or an alkyl grouphaving 1 to 3 carbon atoms, {circle around (3)} an amino group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, {circle around (4)} a hydroxyl group which is unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, {circle around(5)} a thiol group which is unsubstituted or substituted by an alkylgroup having 1 to 3 carbon atoms, or {circle around (6)} a halogen; andwherein each of the above (5), (6), (7) and (8) is unsubstituted orsubstituted by C₁₋₃ alkyl}, or a salt thereof; admixed with (ii) anantiulcer agent.
 4. A composition, comprising (i) a compound of theformula:

wherein: A is an aromatic group which is unsubstituted or substituted by(1) a hydroxyl group, (2) a halogen atom, (3) a nitro group, (4) a cyanogroup, (5) a C₁₋₄ alkyl group which is unsubstituted or substituted by 1to 5 halogens, (6) a C₁₋₄ alkoxy group which is unsubstituted orsubstituted by 1 to 5 halogens, (7) a benzyloxy group, (8) a C₁₋₄ alkoxycarbonyl group, (9) a methylene dioxo or (10) ethylene dioxo; R¹ and R²are independently (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₄₋₆ cycloalkadienyl group,or (8) an aryl group {wherein each of the above (2), (3), (4), (5), (6),(7) and (8) is unsubstituted or substituted by 1 to 5 substituentsselected from the group consisting of {circle around (1)} an aryl groupwhich is unsubstituted or substituted by 1 to 2 substituents selectedfrom the group consisting of an alkoxy group having 1 to 3 carbon atoms,a halogen atom, and an alkyl group having 1 to 3 carbon atoms, {circlearound (2)} a C₃₋₇ cycloalkyl or C₃₋₆ cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} an amino group which is unsubstituted or substitutedby an alkyl group having 1 to 3 carbon atoms, {circle around (4)} ahydroxyl group which is unsubstituted or substituted by an alkyl grouphaving 1 to 3 carbon atoms, {circle around (5)} a thiol group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, and {circle around (6)} a halogen; and wherein each of the above(5), (6), (7) and (8) is unsubstituted or substituted by 1 to 5 C₁₋₃alkyls}; R^(3′) is (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₃₋₆ cycloalkadienyl, or (8)an aryl group {wherein each of the above (2), (3), (4), (5), (6), (7)and (8) is unsubstituted or substituted by {circle around (1)} an arylgroup which is unsubstituted or substituted by an alkoxy group having 1to 3 carbon atoms, a halogen atom, or an alkyl group having 1 to 3carbon atoms, {circle around (2)} a cycloalkyl or cycloalkenyl groupwhich is unsubstituted or substituted by an alkoxy group having 1 to 3carbon atoms, a halogen atom, or an alkyl group having 1 to 3 carbonatoms, {circle around (3)} an amino group which is unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, {circle around(4)} a hydroxyl group which is unsubstituted or substituted by an alkylgroup having 1 to 3 carbon atoms, {circle around (5)} a thiol groupwhich is unsubstituted or substituted by an alkyl group having 1 to 3carbon atoms, or {circle around (6)} a halogen; and wherein each of theabove (5), (6), (7) and (8) is unsubstituted or substituted by C₁₋₃alkyl}; and R^(4′) is (9) a C₁₋₈ alkanoyl group, (10) a C₃₋₆ alkenoylgroup, (11) a C₄₋₇ cycloalkanecarbonyl group, (12) a C₁₋₄ alkanesulfonylgroup, (13) a C₇₋₁₁ aroyl group, (14) a C₆₋₈ aryl-C₂₋₅ alkanoyl group,(15) a C₆₋₈ aryl-C₃₋₅ alkenoyl group, (16) a C₆₋₈ arenesulfonyl group,(17) carbamoyl, (18 N-monosubstituted carbamoyl group {whose substituentis {circle around (1)} a C₁₋₆ alkyl group, {circle around (2)} a C₃₋₆cycloalkyl group, {circle around (3)} an aryl group, or {circle around(4)} an aralkyl group, wherein each of the above {circle around (3)} and{circle around (4)} is unsubstituted or substituted by a hydroxyl group,an amino group (which is unsubstituted or substituted by 1 or 2substituents selected from the group consisting of a C₁₋₄ alkyl, formyl,acetyl, propionyl and benzoyl), a halogen, nitro, cyano, a C₁₋₄ alkyl(which is unsubstituted or substituted by 1 to 5 halogens) or C₁₋₄alkoxy (which is unsubstituted or substituted by 1 to 5 halogens)}, (19)N,N-disubstitutional carbamoyl group {wherein one of the substituents is{circle around (1)} C₁₋₆ alkyl group, {circle around (2)} C₃₋₆cycloalkyl group, {circle around (3)} aryl group, or {circle around (4)}aralkyl group, in which each of the above {circle around (3)} and{circle around (4)} is unsubstituted or substituted by a hydroxyl group,an amino group (which is unsubstituted or substituted by 1 or 2substituents selected from the group consisting of a C₁₋₄ alkyl, formyl,acetyl, propionyl and benzoyl), a halogen, nitro, cyano, a C₁₋₄ alkylwhich is unsubstituted or substituted by 1 to 5 halogens, or C₁₋₄ alkoxy(which is unsubstituted or substituted by 1 to 5 halogens), and theother substituent is a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group, or aC₆₋₁₀ aralkyl group}, or a salt thereof; admixed with (ii) an antiulceragent.
 5. A composition, comprising (i) a compound of the formula:

wherein: A is an indolyl group which is unsubstituted or substituted by(1) a hydroxyl group, (2) a halogen atom, (3) a nitro group, (4) a cyanogroup, (5) a C₁₋₄ alkyl group which is unsubstituted or substituted by 1to 5 halogens, (6) a C₁₋₄ alkoxy group which is unsubstituted orsubstituted by 1 to 5 halogens, (7) a benzyloxy group, (8) a C₁₋₄ alkoxycarbonyl group, (9) a methylene dioxo or (10) ethylene dioxo; R¹ and R²are independently (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alknyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₄₋₆ cycloalkadienyl group,or (8) an aryl group {wherein each of the above (2), (3), (4), (5), (6),(7) and (8) is unsubstituted or substituted by 1 to 5 substituentsselected from the group consisting of {circle around (1)} an aryl groupwhich is unsubstituted or substituted by 1 to 2 substituents selectedfrom the group consisting of an alkoxy group having 1 to 3 carbon atoms,a halogen atom, and an alkyl group having 1 to 3 carbon atoms, {circlearound (2)} a C₃₋₇ cycloalkyl or C₃₋₆ cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} an amino group which is unsubstituted or substitutedby an alkyl group having 1 to 3 carbon atoms, {circle around (4)} ahydroxyl group which is unsubstituted or substituted by an alkyl grouphaving 1 to 3 carbon atoms, {circle around (5)} a thiol group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, and {circle around (6)} a halogen; and wherein each of the above(5), (6), (7) and (8) is unsubstituted or substituted by 1 to 5 C₁₋₃alkyls}, R^(3′) is (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₃₋₆ cycloalkadienyl, (8) anaryl group {wherein each of the above (2), (3), (4), (5), (6), (7) and(8) is unsubstituted or substituted by {circle around (1)} an aryl groupwhich is unsubstituted or substituted by an alkoxy group having 1 to 3carbon atoms, a halogen atom, or an alkyl group having 1 to 3 carbonatoms, {circle around (2)} a cycloalkyl or cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} a hydroxyl group which is unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, {circle around(4)} a thiol group which is unsubstituted or substituted by an alkylgroup having 1 to 3 carbon atoms, or {circle around (5)} a halogen; andwherein each of the above (5), (6), (7) and (8) is unsubstituted orsubstituted by C₁₋₃ alkyl}; and R^(4′″) is (24) a carboxyl group, (25) aC₂₋₈ alkoxycarbonyl group, (26) a C₇₋₁₂ aryloxycarbonyl group, or (27) aC₈₋₁₀ aralkyloxycarbonyl group {wherein each of the above (26) and (27)is unsubstituted or substituted by a hydroxyl group, an amino groupwhich may substituted by 1 or 2 substituents selected from the groupconsisting of a C₁₋₄ alkyl, formyl, acetyl, propionyl and benzoyl,halogen, a nitro, cyano, a C₁₋₄ alkyl which is unsubstituted orsubstituted by 1 to 5 halogens, or C₁₋₄ alkoxy which is unsubstituted orsubstituted by 1 to 5 halogens}, or a salt thereof; admixed with (ii) anantiulcer agent.
 6. A composition as in claim 3, wherein: A is indolyl;R¹ and R² independently represent a hydrogen atom or methyl; R^(3′) ismethyl; and R⁴″′ is an esterified carboxyl group.
 7. A composition as inany of claim 3-6, wherein said antiulcer agent is proton pump inhibitor,a Histamine H₂ antagonist or a mucosa-protecting agent.
 8. A method forprevention or treatment of a gastric or duodenal ulcer, gastritis orgastric cancer, in a mammal which comprises administering to a subjectin need an effective amount of a compound of the formula:

wherein: A is an indolyl group which is unsubstituted or substituted by(1) a hydroxyl group, (2) a halogen atom, (3) a nitro group, (4) a cyanogroup, (5) a C₁₋₄ alkyl group which is unsubstituted or substituted by 1to 5 halogens, (6) a C₁₋₄ alkoxy group which is unsubstituted orsubstituted by 1 to 5 halogens, (7) a benzyloxy group, (8) a C₁₋₄ alkoxycarbonyl group, (9) a methylene dioxo or (10) ethylene dioxo; R¹ and R²are independently (1) a hydrogen atom, (2) a C₁₋₇ alkyl group, (3) aC₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) a C₃₋₉ cycloalkylgroup, (6) a C₃₋₆ cycloalkenyl group, (7) a C₄₋₆ cycloalkadienyl group,or (8) an aryl group {wherein each of the above (2), (3), (4), (5), (6),(7) and (8) is unsubstituted or substituted by 1 to 5 substituentsselected from the group consisting of: {circle around (1)} an aryl groupwhich is unsubstituted or substituted by 1 to 2 substituents selectedfrom the group consisting of an alkoxy group having 1 to 3 carbon atoms,a halogen atom, and an alkyl group having 1 to 3 carbon atoms, {circlearound (2)} a C₃₋₇ cycloalkyl or C₃₋₆ cycloalkenyl group which isunsubstituted or substituted by an alkoxy group having 1 to 3 carbonatoms, a halogen atom or an alkyl group having 1 to 3 carbon atoms,{circle around (3)} an amino group which is unsubstituted or substitutedby an alkyl group having 1 to 3 carbon atoms, {circle around (4)} ahydroxyl group which is unsubstituted or substituted by an alkyl grouphaving 1 to 3 carbon atoms, {circle around (5)} a thiol group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, and {circle around (6)} a halogen; and wherein each of the above(5), (6), (7) and (8) is unsubstituted or substituted by 1 to 5 C₁₋₃alkyls}; and R³ and R⁴ are independently (1) a hydrogen atom, (2) a C₁₋₇alkyl group, (3) a C₂₋₆ alkenyl group, (4) a C₂₋₆ alkynyl group, (5) aC₃₋₉ cycloalkyl group, (6) a C₃₋₆ cycloalkenyl group, (7) a C₃₋₆cycloalkadienyl group, (8) an aryl group, (9) a C₁₋₈ alkanoyl group,(10) a C₃₋₆ alkenoyl group, (11) a C₄₋₇ cycloalkanecarbonyl group, (12)a C₁₋₄ alkanesulfonyl group, (13) a C₇₋₁₁ aroyl group, (14) a C₆₋₈aryl-C₂₋₅ alkanoyl group, (15) a C₆₋₈ aryl-C₃₋₅ alkenoyl group, (16) aC₆₋₈ arenesulfonyl group, (17) carbamoyl, (18) N-monosubstitutionalcarbamoyl group {whose substituent is {circle around (1)} a C₁₋₆ alkylgroup, {circle around (2)} a C₃₋₆ cycloalkyl group, {circle around (3)}an aryl group, or {circle around (4)} an aralkyl group, wherein each ofthe above {circle around (3)} and {circle around (4)}is unsubstituted orsubstituted by a hydroxyl group, an amino group (which is unsubstitutedor substituted by 1 or 2 substituents selected from the group consistingof a C₁₋₄ alkyl, formyl, acetyl, propionyl and benzoyl), a halogen, anitro, a cyano, a C₁₋₄ alkyl (which is unsubstituted or substituted by 1to 5 halogens), or C₁₋₄ alkoxy (which is unsubstituted or substituted by1 to 5 halogens)}, (19) N,N-disubstitutional carbamoyl group {in whichone of the substituents is {circle around (1)} a C₁₋₆ alkyl, {circlearound (2)} a C₃₋₆ cycloalkyl group, {circle around (3)} an aryl group,or {circle around (4)} aralkyl group, wherein each of the above {circlearound (3)} and {circle around (4)} is unsubstituted or substituted by ahydroxyl group, an amino group (which is unsubstituted or substituted by1 or 2 substituents selected from the group consisting of a C₁₋₄ alkyl,formyl, acetyl, propionyl and benzoyl), a halogen, a nitro, a cyano,C₁₋₄ alkyl (which is unsubstituted or substituted by 1 to 5 halogens),or C₁₋₄ alkoxy (which is unsubstituted or substituted by 1 to 5halogens), and the other substituent is a C₁₋₆ alkyl group, a C₃₋₆cycloalkyl group, or a C₆₋₁₀ aralkyl group}, (20 a carboxyl group, (21)a C₂₋₈ alkoxycarbonyl group, (22) a C₇₋₁₂ aryloxycarbonyl group, or (23)a C₈₋₁₀ aralkyloxycarbonyl group {wherein each of the above (2), (3),(4), (5), (6), (7) and (8) is unsubstituted or substituted by the groupconsisting of: {circle around (1)} an aryl group which is unsubstitutedor substituted by an alkoxy group having 1 to 3 carbon atoms, a halogenatom, or an alkyl group having 1 to 3 carbon atoms, {circle around (2)}a cycloalkyl or cycloalkenyl group which is unsubstituted or substitutedby an alkoxy group having 1 to 3 carbon atoms, a halogen atom, or analkyl group having 1 to 3 carbon atoms, {circle around (3)} an aminogroup which is unsubstituted or substituted by, an alkyl group having 1to 3 carbon atoms, {circle around (4)} a hydroxyl group which isunsubstituted or substituted by an alkyl group having 1 to 3 carbonatoms, {circle around (5)} a thiol group which is unsubstituted orsubstituted by an alkyl group having 1 to 3 carbon atoms, and {circlearound (6)} a halogen; wherein each of the above (5), (6), (7) and (8)is unsubstituted or substituted by C₁₋₃ alkyl; and wherein each of theabove (22) and (23) is unsubstituted or substituted by the groupconsisting of a hydroxyl group, an amino group which may substituted by1 or 2 substituents selected from the group consisting of a C₁₋₄ alkyl,formyl, acetyl, propionyl and benzolyl, a halogen, a nitro, cyano, aC₁₋₄ alkyl which is unsubstituted or substituted by 1 to 5 halogens, andC₁₋₄ alkoxy which is unsubstituted or substituted by 1 to 5 halogens},or a salt thereof; and a pharmacologically acceptable diluent, excipientor carrier.
 9. A method as in claim 8, wherein: A represents indolylwhich is unsubstituted or substituted by 1 to 3 substituents selectedfrom the group consisting of hydroxyl, halogen, nitro, cyano, C₁₋₄ alkylwhich is unsubstituted or substituted by 1 to 5 halogens, and C₁₋₄alkoxy which is unsubstituted or substituted by 1 to 5 halogens; R¹ andR² independently represent hydrogen, C₁₋₇ alkyl which is unsubstitutedor substituted by 1 to 5 halogens; and R³ and R⁴ independently representhydrogen or C₁₋₇ alkyl.
 10. A method as claimed in claim 9, wherein: Ais indolyl; R¹ and R³ are hydrogen; and R² and R⁴ are independently C₁₋₇alkyl.
 11. A method as in claim 10, wherein A is 3-indolyl; and R² andR⁴ are methyl.
 12. A method as in claim 8, wherein the compound isindolmycin.
 13. A method as in claim 8, wherein the disease is gastricor duodenal ulcer.
 14. A method as in any one of claims 8 or 9-13,wherein compound (I) is administered in combination with anantibacterial agent.
 15. A method as in any one of claims 8 or 9-13,wherein compound (I) is administered in combination with antiulceragent.
 16. A method as in any one of claims 8 or 9-13, wherein compound(I) is administered in combination with an antibacterial agent and anantiulcer agent.